EP4659809A2 - Steroids and protein-conjugates thereof - Google Patents

Steroids and protein-conjugates thereof

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Publication number
EP4659809A2
EP4659809A2 EP25196812.9A EP25196812A EP4659809A2 EP 4659809 A2 EP4659809 A2 EP 4659809A2 EP 25196812 A EP25196812 A EP 25196812A EP 4659809 A2 EP4659809 A2 EP 4659809A2
Authority
EP
European Patent Office
Prior art keywords
examples
alkyl
formula
compound
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP25196812.9A
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German (de)
English (en)
French (fr)
Inventor
Amy Han
William Olson
Andrew MURPHY J.
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Regeneron Pharmaceuticals Inc
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Regeneron Pharmaceuticals Inc
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Application filed by Regeneron Pharmaceuticals Inc filed Critical Regeneron Pharmaceuticals Inc
Publication of EP4659809A2 publication Critical patent/EP4659809A2/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0088—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing unsubstituted amino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/0026—Oxygen-containing hetero ring cyclic ketals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/0026—Oxygen-containing hetero ring cyclic ketals
    • C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17

Definitions

  • novel steroids Provided herein are novel steroids, protein conjugates thereof, and methods for treating diseases, disorders, and conditions comprising administering the steroids and conjugates.
  • ADCs Antibody-drug conjugates
  • ADCETRIS ® Bossetimab vedotin
  • KADCYLA ® ado-trastuzumab emtansine
  • Glucocorticoids are small molecule steroids that bind to glucocorticoid receptors (GRs) and are utilized in anti-inflammatory and immunosuppressive therapies.
  • GRs glucocorticoid receptors
  • Glucocorticoid treatments are compromised by toxicities to most organ systems.
  • novel glucocorticoids as well as novel therapies that minimize the side effects arising from glucocorticoid administration, particularly those arising from activating glucocorticoid receptors in non-target cells.
  • the instant disclosure provides solutions to the aforementioned needs as well as other unmet needs in the field to which the instant disclosure pertains. Included in the instant disclosure are antibody-drug conjugates comprising glucocorticoid payloads.
  • the compounds have the structure of Formula (A): or a pharmaceutically acceptable salt, solvate, stereoisomer, or derivative thereof, wherein:
  • the compounds are protein-drug conjugates, e.g., antibody-drug conjugates, comprising an antigen-binding protein, e.g., antibody and a compound of Formula (A).
  • the compounds are protein-drug conjugates, e.g., antibody-drug conjugates, comprising an antigen-binding protein, e.g., antibody, a compound of Formula (A), and a cyclodextrin moiety.
  • alkyl refers to a monovalent and saturated hydrocarbon radical moiety. Alkyl is optionally substituted and can be linear, branched, or cyclic, i.e., cycloalkyl. Alkyl includes, but is not limited to, those having 1-20 carbon atoms, i.e., C 1-20 alkyl; 1-12 carbon atoms, i.e., C 1-12 alkyl; 1-8 carbon atoms, i.e., C 1-8 alkyl; 1-6 carbon atoms, i.e., C 1-6 alkyl; and 1-3 carbon atoms, i.e., C 1-3 alkyl.
  • alkyl moieties include, but are not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t- butyl , i- butyl, a pentyl moiety, a hexyl moiety, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Alkylene is divalent alkyl.
  • haloalkyl refers to alkyl, as defined above, wherein the alkyl includes at least one substituent selected from a halogen, e.g., F, Cl, Br, or I.
  • alkenyl refers to a monovalent hydrocarbon radical moiety containing at least two carbon atoms and one or more non-aromatic carbon-carbon double bonds. Alkenyl is optionally substituted and can be linear, branched, or cyclic. Alkenyl includes, but is not limited to, those having 2-20 carbon atoms, i.e., C 2-20 alkenyl; 2-12 carbon atoms, i.e., C 2-12 alkenyl; 2-8 carbon atoms, i.e., C 2-8 alkenyl; 2-6 carbon atoms, i.e., C 2-6 alkenyl; and 2-4 carbon atoms, i.e., C 2-4 alkenyl. Examples of alkenyl moieties include, but are not limited to vinyl, propenyl, butenyl, and cyclohexenyl. "Alkenylene” is divalent alkenyl.
  • alkynyl refers to a monovalent hydrocarbon radical moiety containing at least two carbon atoms and one or more carbon-carbon triple bonds. Alkynyl is optionally substituted and can be linear, branched, or cyclic.
  • Alkynyl includes, but is not limited to, those having 2-20 carbon atoms, i.e., C 2-20 alkynyl; 2-12 carbon atoms, i.e., C 2-12 alkynyl; 2-8 carbon atoms, i.e., C 2-8 alkynyl; 2-6 carbon atoms, i.e., C 2-6 alkynyl; and 2-4 carbon atoms, i.e., C 2-4 alkynyl.
  • alkynyl moieties include, but are not limited to ethynyl, propynyl, and butynyl.
  • Alkynylene is divalent alkynyl.
  • alkoxy refers to a monovalent and saturated hydrocarbon radical moiety wherein the hydrocarbon includes a single bond to an oxygen atom and wherein the radical is localized on the oxygen atom,e.g, CH 3 CH 2 -O ⁇ for ethoxy.
  • Alkoxy substituents bond to the compound which they substitute through this oxygen atom of the alkoxy substituent.
  • Alkoxy is optionally substituted and can be linear, branched, or cyclic, i.e., cycloalkoxy.
  • Alkoxy includes, but is not limited to, those having 1-20 carbon atoms, i.e., C 1-20 alkoxy; 1-12 carbon atoms, i.e., C 1-12 alkoxy; 1-8 carbon atoms, i.e., C 1-8 alkoxy; 1-6 carbon atoms, i.e., C 1-6 alkoxy; and 1-3 carbon atoms, i.e., C 1-3 alkoxy.
  • alkoxy moieties include, but are not limited to methoxy, ethoxy, n -propoxy, i -propoxy, n -butoxy, s-butoxy, t -butoxy, i -butoxy, a pentoxy moiety, a hexoxy moiety, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.
  • haloalkoxy refers to alkoxy, as defined above, wherein the alkoxy includes at least one substituent selected from a halogen, e.g., F, Cl, Br, or I.
  • aryl refers to a monovalent moiety that is a radical of an aromatic compound wherein the ring atoms are carbon atoms.
  • Aryl is optionally substituted and can be monocyclic or polycyclic, e.g., bicyclic or tricyclic.
  • aryl moieties include, but are not limited to those having 6 to 20 ring carbon atoms, i.e., C 6-20 aryl; 6 to 15 ring carbon atoms, i.e., C 6-15 aryl, and 6 to 10 ring carbon atoms, i.e., C 6-10 aryl.
  • Examples of aryl moieties include, but are limited to phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, and pyrenyl.
  • arylalkyl refers to an monovalent moiety that is a radical of an alkyl compound, wherein the alkyl compound is substituted with an aromatic substituent, i.e., the aromatic compound includes a single bond to an alkyl group and wherein the radical is localized on the alkyl group.
  • An arylalkyl group bonds to the illustrated chemical structure via the alkyl group.
  • An arylalkyl can be represented by the structure, e.g., wherein B is an aromatic moiety, e.g., phenyl.
  • Arylalkyl is optionally substituted, i.e., the aryl group and/or the alkyl group, can be substituted as disclosed herein. Examples of arylalkyl include, but are not limited to, benzyl.
  • aryloxy refers to a monovalent moiety that is a radical of an aromatic compound wherein the ring atoms are carbon atoms and wherein the ring is substituted with an oxygen radical, i.e., the aromatic compound includes a single bond to an oxygen atom and wherein the radical is localized on the oxygen atom, e.g., for phenoxy.
  • Aryloxy substituents bond to the compound which they substitute through this oxygen atom. Aryloxy is optionally substituted.
  • Aryloxy includes, but is not limited to those having 6 to 20 ring carbon atoms, i.e., C 6-20 aryloxy; 6 to 15 ring carbon atoms, i.e., C 6-15 aryloxy, and 6 to 10 ring carbon atoms, i.e ., C 6-10 aryloxy.
  • aryloxy moieties include, but are not limited to phenoxy, naphthoxy, and anthroxy.
  • R a R b N-aryloxy refers to a monovalent moiety that is a radical of an aromatic compound wherein the ring atoms are carbon atoms and wherein the ring is substituted with an R a R b N- substituent and an oxygen radical, i.e., the aromatic compound includes a single bond to an R a R b N- substituent and a single bond to an oxygen atom and wherein the radical is localized on the oxygen atom, e.g. , R a R b N-aryloxy substituents bond to the compound which they substitute through this oxygen atom.
  • R a R b N-aryloxy is optionally substituted.
  • R a R b N-aryloxy includes, but is not limited to those having 6 to 20 ring carbon atoms, 6 to 15 ring carbon atoms; and 6 to 10 ring carbon atoms.
  • An example of an R a R b N-aryloxy moiety includes, but is not limited to 4-(dimethyl-amino)-phenoxy,
  • arylene refers to a divalent moiety of an aromatic compound wherein the ring atoms are only carbon atoms.
  • Arylene is optionally substituted and can be monocyclic or polycyclic, e.g., bicyclic or tricyclic.
  • Examples of arylene moieties include, but are not limited to those having 6 to 20 ring carbon atoms, i.e., C 6-20 arylene; 6 to 15 ring carbon atoms, i.e., C 6-15 arylene, and 6 to 10 ring carbon atoms, i.e., C 6-10 arylene.
  • heteroalkyl refers to an alkyl in which one or more carbon atoms are replaced by heteroatoms.
  • heteroalkenyl refers to an alkenyl in which one or more carbon atoms are replaced by heteroatoms.
  • heteroalkynyl refers to an alkynyl in which one or more carbon atoms are replaced by heteroatoms. Suitable heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur atoms. Heteroalkyl is optionally substituted.
  • heteroalkyl moieties include, but are not limited to, aminoalkyl, sulfonylalkyl, sulfinylalkyl.
  • heteroalkyl moieties also include, but are not limited to, methylamino, methylsulfonyl, and methylsulfinyl.
  • heteroaryl refers to a monovalent moiety that is a radical of an aromatic compound wherein the ring atoms contain carbon atoms and at least one oxygen, sulfur, nitrogen, or phosphorus atom.
  • heteroaryl moieties include, but are not limited to those having 5 to 20 ring atoms; 5 to 15 ring atoms; and 5 to 10 ring atoms. Heteroaryl is optionally substituted.
  • heteroarylene refers to an arylene in which one or more ring atoms of the aromatic ring are replaced with an oxygen, sulfur, nitrogen, or phosphorus atom. Heteroarylene is optionally substituted.
  • heterocycloalkyl refers to a cycloalkyl in which one or more carbon atoms are replaced by heteroatoms. Suitable heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur atoms. Heterocycloalkyl is optionally substituted. Examples of heterocycloalkyl moieties include, but are not limited to, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, dioxolanyl, dithiolanyl, oxanyl, or thianyl.
  • N-containing heterocycloalkyl refers to a cycloalkyl in which one or more carbon atoms are replaced by heteroatoms and wherein at least one heteroatom is a nitrogen atom. Suitable heteroatoms in addition to nitrogen, include, but are not limited to oxygen and sulfur atoms. N-containing heterocycloalkyl is optionally substituted. Examples of N-containing heterocycloalkyl moieties include, but are not limited to, morpholinyl, piperidinyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, or thiazolidinyl.
  • optionally substituted when used to describe a radical moiety, e.g., optionally substituted alkyl, means that such moiety is optionally bonded to one or more substituents.
  • substituents include, but are not limited to halo, cyano, nitro, haloalkyl, azido, epoxy, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or wherein R A , R B , and R C are, independently at each occurrence, a hydrogen atom, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, or R A and R B , together with the atoms to which they are bonded, form a saturated or unsaturated carbocyclic ring, wherein the ring is optionally substituted and wherein one or more ring atoms is optionally replaced with a heteroatom.
  • a radical moiety is optionally substituted with an optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted saturated or unsaturated carbocyclic ring
  • the substituents on the optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted saturated or unsaturated carbocyclic ring, if they are substituted, are not substituted with substituents which are further optionally substituted with additional substituents.
  • the substituent bonded to the group is unsubstituted unless otherwise specified.
  • binding agent refers to any molecule capable of binding with specificity to a given binding partner.
  • the binding agent is an antibody, or an antigen binding fragment thereof.
  • linker refers to a divalent moiety that covalently links the binding agent to the steroid described herein.
  • amide synthesis conditions refers to reaction conditions suitable facilitate the formation of an amide, e.g., by the reaction of a carboxylic acid, activated carboxylic acid, or acyl halide with an amine.
  • amide synthesis conditions refers to reaction conditions suitable to facilitate the formation of an amide bond between a carboxylic acid and an amine.
  • the carboxylic acid is first converted to an activated carboxylic acid before the activated carboxylic acid reacts with an amine to form an amide.
  • Suitable conditions to effect the formation of an amide include, but are not limited to, those utilizing reagents to effect the reaction between a carboxylic acid an amine, including, but not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexaflu
  • a carboxylic acid is first converted to an activated carboxylic ester before reacting with an amine to form an amide bond.
  • the carboxylic acid is reacted with a reagent.
  • the reagent activates the carboxylic acid by deprotonating the carboxylic acid and then forming a product complex with the deprotonated carboxylic acid as a result of nucleophilic attack by the deprotonated carboxylic acid onto the protonated reagent.
  • this activated ester is more susceptible subsequently to nucleophilic attack by an amine than the carboxylic acid is before it is converted. This results in amide bond formation.
  • the carboxylic acid is described as activated.
  • Exemplary reagents include DCC and DIC.
  • terapéuticaally effective amount refers to an amount (of a compound) that is sufficient to provide a therapeutic benefit to a patient in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder.
  • pharmaceutically acceptable derivative refers to any form, e.g., ester or prodrug of a compound, which provides said compound upon administration to a patient.
  • salt refers to any salt suitable for administration to a patient. Suitable salts include, but are not limited to, those disclosed in. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66:1 , incorporated herein by reference.
  • salts include, but are not limited to, acid-derived, base-derived, organic, inorganic, amine, and alkali or alkaline earth metal salts, including but not limited to calcium salts, magnesium salts, potassium salts, sodium salts, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid, and the like.
  • a phenyl group that is substituted with a propyl group depicted as: has the following structure:
  • illustrations showing substituents bonded to a cyclic group e.g., aromatic, heteroaromatic, fused ring, and saturated or unsaturated cycloalkyl or heterocycloalkyl
  • substituents bonded to a cyclic group e.g., aromatic, heteroaromatic, fused ring, and saturated or unsaturated cycloalkyl or heterocycloalkyl
  • a bond between ring atoms are meant to indicate, unless specified otherwise, that the cyclic group may be substituted with that substituent at any ring position in the cyclic group or on any ring in the fused ring group, according to techniques set forth herein or which are known in the field to which the instant disclosure pertains.
  • the substituent R 1 are described generically, i.e., not directly attached to any vertex of the bond line structure, i.e., specific ring carbon atom, includes the following, non-limiting examples of, groups in which the substituent R 1 is bonded to a specific ring carbon atom:
  • the group, wherein subscript n is an integer from 0 to 19 and in which the positions of substituent R 5 are described generically, i.e., depicted as not directly attached to any vertex of the bond line structure, includes the following, non-limiting examples of, groups in which the substituent R 5 is bonded to a specific ring carbon atom:
  • the phrase "reactive linker,” or the abbreviation "RL” refers to a monovalent group that comprises a reactive group and linking group, depicted as wherein RG is the reactive group and L is the linking group.
  • the linking group is any divalent moiety that bridges the reactive group to a payload.
  • the reactive linkers (RL), together with the payloads to which they are bonded, comprise intermediates ("linker-payloads") useful as synthetic precursors for the preparation of the antibody steroid conjugates described herein.
  • the reactive linker contains a reactive group (“RG”), which is a functional group or moiety that reacts with a reactive portion of an antibody, modified antibody, or antigen binding fragment thereof.
  • the "reactive group” is a functional group or moiety (e.g., maleimide or NHS ester) that reacts with a cysteine or lysine residue of an antibody or antigen-binding fragment thereof.
  • the "reactive group” is a functional group or moiety that is capable of undergoing a click chemistry reaction.
  • the reactive group is an alkyne that is capable of undergoing a 1,3 cycloaddition reaction with an azide.
  • Such suitable reactive groups include, but are not limited to, strained alkynes, e.g., those suitable for strain-promoted alkyne-azide cycloadditions (SPAAC), cycloalkynes, e.g., cyclooctynes, benzannulated alkynes, and alkynes capable of undergoing 1,3 cycloaddition reactions with azides in the absence of copper catalysts.
  • Suitable alkynes also include, but are not limited to, DIBAC, DIBO, BARAC, DIFO, substituted, e.g., fluorinated alkynes, aza-cycloalkynes, BCN, and derivatives thereof.
  • Linker-payloads comprising such reactive groups are useful for conjugating antibodies that have been functionalized with azido groups.
  • Such functionalized antibodies include antibodies functionalized with azido-polyethylene glycol groups.
  • such functionalized antibody is derived by reacting an antibody comprising at least one glutamine residue, e.g., heavy chain Q295 (EU numbering), with a compound according to the formula H 2 N-LL-N 3 , wherein LL is a divalent polyethylene glycol group, in the presence of the enzyme transglutaminase.
  • the reactive group is an alkyne, e.g., which can react via click chemistry with an azide, e.g., to form a click chemistry product, e.g., its regioisomer, or mixture thereof.
  • the reactive group is an alkyne, e.g., which can react via click chemistry with an azide, e.g., to form a click chemistry product, e.g.,
  • the reactive group is an alkyne, e.g., which can react via click chemistry with an azide, e.g., to form a click chemistry product, e.g., its regioisomer, or mixture thereof.
  • the reactive group is a functional group, e.g., which reacts with a cysteine residue on an antibody or antigen-binding fragment thereof, to form a bond thereto, e.g., wherein Ab refers to an antibody or antigen-binding fragment thereof and S refers to the S atom on a cysteine residue through which the functional group bonds to the Ab.
  • the reactive group is a functional group, e.g., which reacts with a lysine residue on an antibody or antigen-binding fragment thereof, to form a bond thereto, e.g., wherein Ab refers to an antibody or antigen-binding fragment thereof and N refers to the N atom on a lysine residue through which the functional group bonds to the Ab.
  • binding agent linker refers to any divalent group or moiety that links, connects, or bonds a binding agent (e.g., an antibody or an antigen-binding fragment thereof) with a payload compound set forth herein (e.g., steroid).
  • a binding agent e.g., an antibody or an antigen-binding fragment thereof
  • a payload compound set forth herein e.g., steroid
  • suitable binding agent linkers for the antibody conjugates described herein are those that are sufficiently stable to exploit the circulating half-life of the antibody and, at the same time, capable of releasing its payload after antigen-mediated internalization of the conjugate. Linkers can be cleavable or non-cleavable.
  • Cleavable linkers are linkers that are cleaved by intracellular metabolism following internalization, e.g., cleavage via hydrolysis, reduction, or enzymatic reaction.
  • Non-cleavable linkers are linkers that release an attached payload via lysosomal degradation of the antibody following internalization.
  • Suitable linkers include, but are not limited to, acid-labile linkers, hydrolysis-labile linkers, enzymatically cleavable linkers, reduction labile linkers, self-immolative linkers, and non-cleavable linkers.
  • Suitable linkers also include, but are not limited to, those that are or comprise glucuronides, succinimide-thioethers, polyethylene glycol (PEG) units, hydrazones, mal-caproyl units, disulfide units (e.g ., -S-S-, -S-C(R 1 R 2 ) -, wherein R 1 and R 2 are independently hydrogen or hydrocarbyl), carbamate units, para-amino-benzyl units (PAB), phosphate units, e.g., mono-, bis-, or tris- phosphate units, and peptide units, e.g., peptide units containing two, three four, five, six, seven, eight, or more amino acids, including but not limited to valine-citrulline and units.
  • the binding agent linker (BL) comprises a moiety that is formed by the reaction of the reactive group (RG) of a reactive linker (RL) and reactive portion of the binding agent, e.g., antibody, modified antibody, or antigen binding fragment thereof.
  • the BL comprises the following moiety: its regioisomer, or mixture thereof, wherein is the bond to the binding agent. In some examples, the BL comprises the following moiety: its regioisomer, or mixture thereof, wherein is the bond to the binding agent. In some examples, the BL comprises the following moiety: its regioisomer, or mixture thereof, wherein is the bond to the binding agent. In some examples, the BL comprises the following moiety: its regioisomer, or mixture thereof, wherein is the bond to the binding agent. In some examples, the BL comprises the following moiety: wherein is the bond to the cysteine of the antibody or antigen-binding fragment thereof.
  • the BL comprises the following moiety: wherein is the bond to the lysine of the antibody or antigen-binding fragment thereof.
  • the bond to the binding agent is direct or via a linker.
  • the binding agent is modified with an azide to facilitate linkage to BL. Examples are described below.
  • the compound of Formula (A) has the structure of Formula ( A 1 ): wherein R 1 -R 3 are as defined above and R 5A and R 5B are each, independently, halo or a hydrogen atom.
  • R 5A and R 5B are hydrogen atoms. In some embodiments of the compound of Formula ( A 1 ), R 5A and R 5B are fluoro. In some embodiments of the compound of Formula ( A 1 ), R 5A is a hydrogen atom and R 5B is fluoro.
  • R 1 is alkylene-C(O)-O- or -OH and R 2 is alkyl.
  • R 1 and R 2 together form wherein R 4 is aryl, arylalkyl, or alkyl, wherein the aryl, arylalkyl, and alkyl are optionally substituted with -NR a R b .
  • R 4 is -aryl- NR a R b .
  • R 4 is -phenyl- NR a R b .
  • R 1 and R 2 together form wherein R 4 is
  • R 3 is -OH, -NR a R b , R Z -C(O)-X-, or wherein R P is halo, t is an integer from 0 to 2, R a is H, R b is H or alkyl, X is O or NH, and R Z is alkyl.
  • R 3 is -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 ,
  • R 1 and R 2 together form wherein R 4 is aryl, arylalkyl, or alkyl, wherein the aryl, arylalkyl, and alkyl are optionally substituted with -NR a R b ;
  • R 3 is -OH, -NR a R b , R Z -C(O)-X-, or wherein R P is halo, t is an integer from 0 to 2, R a is H, R b is H or alkyl, X is O or NH, and R Z is alkyl; and
  • R 5 independently at each occurrence, is fluoro or a hydrogen atom.
  • n is an integer from 0 to 4 and R 3 is -OH or R Z -C(O)-O-; wherein R Z is alkyl. In certain embodiments, n is 0 or 1.
  • n is an integer from 1-4 and R 3 is -OH or R Z -C(O)-O-; wherein R Z is alkyl. In certain embodiments, n is 2.
  • R 3 is -NR a R b and R 4 is alkyl, wherein R a and R b are each, independently, a hydrogen atom or alkyl, or R a and R b , taken together form a 3-7 membered ring.
  • R 4 is C 1-4 alkyl.
  • R 4 is propyl.
  • R 3 is -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 .
  • R 4 is alkyl
  • R P1 is halo or a hydrogen atom
  • R P2 is -NR a R b or -OH, wherein R a and R b are each, independently, a hydrogen atom or alkyl.
  • R 4 is C 1-4 alkyl and R P2 is -NH 2 .
  • R 3 is R Z C(O)X-, or NR a R b , wherein X is O or NR a , is aryl or heteroaryl, R P is halo, t is an integer from 0-2, R a and R b are each, independently, a hydrogen atom or alkyl, R Z is alkyl, and R Q is alkoxy, and R 4 is alkyl.
  • R 3 is R Z C(O)X-, or NR a R b , wherein X is O or NR a , is aryl or heteroaryl, R P is halo, t is an integer from 0-2, R a and R b are each, independently, a hydrogen atom or alkyl, R Z is alkyl, and R Q is alkoxy, and R 4 is alkyl.
  • R 3 is R Z C(O)X-, or NR a R b , wherein X is O or NR a , is aryl or
  • R 3 is wherein X is O or NR a , is aryl or heteroaryl, R P is halo, t is an integer from 0-2, R a and R b are each, independently, a hydrogen atom or alkyl, R 5A is a hydrogen atom or fluoro, and R 5B is fluoro.
  • R 3 is wherein X is O or NR a , is aryl or heteroaryl, R P is halo, t is an integer from 0-2, R a and R b are each, independently, a hydrogen atom or alkyl, R 5A is a hydrogen atom or fluoro, and R 5B is fluoro.
  • R 3 is wherein X is O or NR a , is aryl or heteroaryl, R P is halo, t is an integer from 0-2, R a and R b are each, independently, a hydrogen atom or alkyl, R 5A is a hydrogen atom or fluoro, and
  • R 1 and R 2 are, independently, selected from -H, alkyl, alkyl-C(O)-O-, -OH, and halo. In some other examples, R 1 and R 2 together form In certain examples, R 1 is -H. In certain other examples, R 1 is alkyl. In some examples, R 1 is alkyl-C(O)-O-. In some other examples, R 1 is -OH. In certain examples, R 1 is halo. In certain other examples, R 1 is -F. In some examples, R 1 is -Cl. In some other examples, R 1 is -Br. In certain examples, R 1 is -I. In certain other examples, R 2 is -OH. In some examples, R 2 is halo. In some other examples, R 2 is -F. In certain examples, R 2 is -Cl. In certain other examples, R 2 is -Br. In some examples, R 2 is -I. In certain other examples, R 2 is -OH. In some examples, R 2
  • R 5 is -OH.
  • R 5 is halo such as but not limited to -F, -Cl, -Br, or -I.
  • R 5 is -F.
  • R 5 is -Cl.
  • R 5 is -Br.
  • R 5 is -I.
  • R 5 is alkyl such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl.
  • R 5 is benzyl.
  • R 3 is selected from -OH, alkyl-C(O)-O-, and R a R b N-aryloxy. In some of these examples, alkyl-C(O)-O- or R a R b N-aryloxy is optionally substituted with halo. In some examples, R 3 is -OH. In some examples, R 3 is alkyl-C(O)-O-. In some examples, R 3 is R a R b N-aryloxy. In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is, R 3 is o
  • R 3 is -OH, alkyl-C(O)-O-, heteroalkyl, -NR a R b , or R a R b N-aryloxy, wherein alkyl-C(O)-O-, heteroalkyl, -NR a R b , or R a R b N-aryloxy is optionally substituted with halo.
  • R a and R b are, independently in each instance, -H or alkyl.
  • R 3 is R a R b N-aryloxy, wherein R a and R b are, independently in each instance, -H or alkyl.
  • R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is . In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is . In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is
  • R 3 is R a R b N-aryloxy, wherein R a and R b are, independently in each instance, -H or alkyl.
  • R 4 is selected from the group consisting of alkyl, aryl, arylalkyl, and an N-containing heterocycloalkyl. In some of these examples, alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl are optionally substituted with -NR a R b .
  • R 4 is alkyl such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. In some examples, R 4 is methyl. In some examples, R 4 is ethyl.
  • R 4 is n-propyl. In some examples, R 4 is i-propyl. In some examples, R 4 is n-butyl. In some examples, R 4 is i-butyl. In some examples, R 4 is t-butyl. In some examples, R 4 is sec-butyl. In some examples, R 4 is pentyl. In some examples, R 4 is hexyl. In some examples, R 4 is heptyl. In some examples, R 4 is octyl, or nonyl. In some examples, R 4 is aryl such as but not limited to phenyl or naphthyl. In some examples, R 4 is phenyl. In some examples, R 4 is naphthyl. In some examples, R 4 is arylalkyl-such as but not limited to benzyl. In some examples, R 4 is N-containing heterocycloalkyl such as but not
  • R 4 is 4-amino-phenyl. In some examples, R 4 is 4-aminophenyl optionally substituted with halo.
  • R 4 is wherein R a and R b are, independently in each instance, H or alkyl.
  • R 4 is
  • R 4 is
  • R 4 is
  • R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is in some examples, R 4 is
  • R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is in some examples, R 4 is
  • R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is in some examples, R 4 is
  • R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is in some examples, R 4 is
  • R 4 is alkyl substituted with amino such as, but not limited to, methyl-amino, ethyl-amino, propyl-amino, butyl-amino, pentyl-amino, hexyl-amino, heptyl-amino, octyl-amino, or nonyl-amino.
  • R 4 is methyl-amino.
  • R 4 is ethyl-amino.
  • R 4 is n-propyl-amino.
  • R 4 is i-propyl-amino.
  • R 4 is n-butyl-amino.
  • R 4 is i-butyl-amino. In some examples, R 4 is t-butyl-amino. In some examples, R 4 is pentyl-amino. In some examples, R 4 is hexyl-amino. In some examples, R 4 is heptyl-amino. In some examples, R 4 is octyl-amino. In some examples, R 4 is nonyl-amino.
  • R 4 is In some examples, R 4 is . In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is
  • R a and R b are, independently in each instance, selected from H and alkyl. In some examples, both R and R b are H. In some examples, both R a and R b are methyl. In some examples, both R a and R b are ethyl. In some examples, both R a and R b are propyl. In some examples, one of R a or R b is -H and the other is alkyl. In some examples, one of R a or R b is -H and the other is methyl. In some examples, one of R a or R b is -H and the other is ethyl. In some examples, one of R a or R b is -H and the other is propyl.
  • n is an integer from 0-19. In some examples, n is 0. In some other examples, n is 1. In certain examples, n is 2. In some other examples, n is 3. In certain examples, n is 4. In some examples, n is 5. In some other examples, n is 6. In certain examples, n is 7. In some other examples, n is 8. In certain examples, n is 9. In some examples, n is 10. In some other examples, n is 11. In certain examples, n is 12. In some other examples, n is 13. In certain examples, n is 14. In some examples, n is 15. In some other examples, n is 16. In certain examples, n is 17. In some other examples, n is 18. In certain examples, n is 19.
  • R 3 is not -OH when R 1 is -OH.
  • R 3 is not -OH when R 1 and R 2 together form wherein R 4 is a C 1-9 alkyl or 4-(dimethyl-amino)-phenyl.
  • R 4 is alkyl, aryl, arylalkyl, or a N-containing heterocycloalkyl.
  • alkyl, aryl, heteroaryl, arylalkyl, or N-containing heterocycloalkyl are optionally substituted with -NR a R b .
  • R 4 is alkyl.
  • R 4 is aryl.
  • R 4 is arylalkyl.
  • R 4 is N-containing heterocycloalkyl.
  • R 4 is alkyl such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. In some examples, R 4 is methyl. In some examples, R 4 is ethyl. In some examples, R 4 is n-propyl. In some examples, R 4 is i-propyl. In some examples, R 4 is n-butyl. In some examples, R 4 is i-butyl. In some examples, R 4 is t-butyl. In some examples, R 4 is sec-butyl. In some examples, R 4 is pentyl.
  • R 4 is hexyl. In some examples, R 4 is heptyl. In some examples, R 4 is octyl, or nonyl. In some examples, R 4 is aryl such as but not limited to phenyl or naphthyl. In some examples, R 4 is phenyl. In some examples, R 4 is naphthyl. In some examples, R 4 is heteroaryl-such as but not limited to thiophene or phenol. In some examples, R 4 is arylalkyl-such as but not limited to benzyl. In some examples, R 4 is N-containing heterocycloalkyl such as but not limited to piperidinyl. In some examples, R 4 is 4-amino-phenyl. In some examples, R 4 is 4-aminophenyl optionally substituted with halo.
  • R 1 and R 2 together form wherein R 4 is selected from the group consisting of alkyl, aryl, arylalkyl, and a N-containing heterocycloalkyl; and wherein alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl are optionally substituted with -NR a R b ; and wherein the stereochemistry of the carbon indicated by * is the R configuration.
  • R 1 and R 2 together form wherein R 4 is selected from the group consisting of alkyl, aryl, arylalkyl, and a N-containing heterocycloalkyl; and wherein alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl are optionally substituted with -NR a R b ; and wherein the stereochemistry of the carbon indicated by * is the S configuration.
  • R 1 and R 2 are, independently, selected from -H, alkyl, alkyl-C(O)-O-, -OH, and halo. In some other examples, R 1 and R 2 together form In certain examples, R 1 is -H. In certain other examples, R 1 is alkyl. In some examples, R 1 is alkyl-C(O)-O-. In some other examples, R 1 is -OH. In certain examples, R 1 is halo. In certain other examples, R 1 is -F. In some examples, R 1 is -Cl.
  • R 1 is -Br. In certain examples, R 1 is -I. In certain other examples, R 2 is -OH. In some examples, R 2 is halo. In some other examples, R 2 is -F. In certain examples, R 2 is -Cl. In certain other examples, R 2 is -Br. In some examples, R 2 is- I.
  • R 5 is -OH.
  • R 5 is halo such as but not limited to -F, -Cl, -Br, or -I.
  • R 5 is -F.
  • R 5 is -Cl.
  • R 5 is -Br.
  • R 5 is -I.
  • R 5 is alkyl such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl.
  • R 3 is selected from -OH, alkyl-C(O)-O-, and R a R b N-aryloxy. In some of these examples, alkyl-C(O)-O- or R a R b N-aryloxy is optionally substituted with halo. In some examples, R 3 is -OH. In some examples, R 3 is alkyl-C(O)-O-. In some examples, R 3 is R a R b N-aryloxy-. In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is R a R b N-aryloxy-. In some examples, R 3 is -NR a R b -aryloxy.
  • R 4 is selected from the group consisting of alkyl, aryl, arylalkyl, and an N-containing heterocycloalkyl. In some of these examples, alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl are optionally substituted with -NR a R b .
  • R 4 is alkyl such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. In some examples, R 4 is methyl. In some examples, R 4 is ethyl.
  • R 4 is n-propyl. In some examples, R 4 is i-propyl. In some examples, R 4 is n-butyl. In some examples, R 4 is i-butyl. In some examples, R 4 is t-butyl. In some examples, R 4 is pentyl. In some examples, R 4 is hexyl. In some examples, R 4 is heptyl. In some examples, R 4 is octyl, or nonyl. In some examples, R 4 is aryl such as but not limited to phenyl or naphthyl. In some examples, R 4 is phenyl. In some examples, R 4 is naphthyl.
  • R 4 is arylalkyl-such as but not limited to benzyl. In some examples, R 4 is N-containing heterocycloalkyl such as but not limited to piperidinyl. In some examples, R 4 is 4-amino-phenyl. In some examples, R 4 is 4-aminophenyl optionally substituted with halo.
  • R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is in some examples, R 4 is
  • R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is in some examples, R 4 is
  • R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is in some examples, R 4 is
  • R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is in some examples, R 4 is
  • R 4 is alkyl substituted with amino such as, but not limited to, methyl-amino, ethyl-amino, propyl-amino, butyl-amino, pentyl-amino, hexyl-amino, heptyl-amino, octyl-amino, or nonyl-amino.
  • R 4 is methyl-amino.
  • R 4 is ethyl-amino.
  • R 4 is n-propyl-amino.
  • R 4 is i-propyl-amino.
  • R 4 is n-butyl-amino.
  • R 4 is i-butyl-amino. In some examples, R 4 is t-butyl-amino. In some examples, R 4 is pentyl-amino. In some examples, R 4 is hexyl-amino. In some examples, R 4 is heptyl-amino. In some examples, R 4 is octyl-amino. In some examples, R 4 is nonyl-amino.
  • R 4 is In some examples, R 4 is . In some examples, R 4 is
  • R a and R b are, independently in each instance, selected from -H or alkyl. In some examples, both R a and R b are -H. In some examples, both R a and R b are methyl. In some examples, both R a and R b are ethyl. In some examples, both R a and R b are propyl. In some examples, one of R a or R b is -H and the other is alkyl. In some examples, one of R a or R b is -H and the other is methyl. In some examples, one of R a or R b is -H and the other is ethyl. In some examples, one of R a or R b is -H and the other is propyl.
  • n is an integer from 0-19. In some examples, n is 0. In some other examples, n is 1. In certain examples, n is 2. In some other examples, n is 3. In certain examples, n is 4. In some examples, n is 5. In some other examples, n is 6. In certain examples, n is 7. In some other examples, n is 8. In certain examples, n is 9. In some examples, n is 10. In some other examples, n is 11. In certain examples, n is 12. In some other examples, n is 13. In certain examples, n is 14. In some examples, n is 15. In some other examples, n is 16. In certain examples, n is 17. In some other examples, n is 18. In certain examples, n is 19.
  • R 3 is not -OH when R 1 is -OH.
  • R 3 is not -OH when R 1 and R 2 together form wherein R 4 is a C 1-9 alkyl or 4-(dimethyl-amino)-phenyl. In some examples, R 4 is In some examples, R 4 is
  • PIa a compound of Formula (PIa), wherein the compound has the structure of Formula (PIb-1) or (PIb-2):
  • PIa a compound of Formula (PIa), wherein the compound has the structure of Formula (PIc-1) or (PIc-2):
  • n is 0. In some examples, n is 1. In some examples, n is 2.
  • set forth herein is a compound of Formula (I), wherein the compound has the structure of Formula (PIe-1) or ( PIe-2 ):
  • set forth herein is a compound of Formula ( PIa ), (PIb-1), (PIb-2), (PIc-1), (PIc-2), (PId-1), (PId-2), (PIe-1), or (PIe-2) wherein R 3 is selected from alkyl-C(O)-O- or R a R b N-aryloxy-; wherein alkyl-C(O)-O-, or R a R b N-aryloxy- are optionally substituted with halo.
  • set forth herein is a compound of Formula ( PIa ), (PIb-1), (PIb-2), (PIc-1), (PIc-2), (PId-1), (PId-2), (PIe-1), or ( PIe-2 ) , wherein R 3 is alkyl-C(O)-O- optionally substituted with halo.
  • set forth herein is a compound of Formula (PIa), (PIb-1), (PIb-2), (PIc-1), (PIc-2), (PId-1), (PId-2), (PIe-1), or ( PIe-2 ) , wherein R 3 is
  • set forth herein is a compound of Formula (PIa), (PIb-1), (PIb-2), (PIc-1), (PIc-2), (PId-1), (PId-2), (PIe-1), or ( PIe-2 ) , wherein R 3 is R a R b N-aryloxy- optionally substituted with halo.
  • set forth herein is a compound of Formula (PIa), (PIb-1), (PIb-2), (PIc-1), (PIc-2), (PId-1), (PId-2), (PIe-1), or (PIe-2), wherein R 3 is
  • set forth herein is a compound of Formula (PIa), (PIb-1), (PIb-2), (PIc-1), (PIc-2), (PId-1), (PId-2), (PIe-1), or (PIe-2), wherein R 3 is
  • set forth herein is a compound of Formula (PIa), (PIb-1), (PIb-2), (PIc-1), (PIc-2), (PId-1), (PId-2), (PIe-1), or (PIe-2), wherein R 3 is selected from -OH, alkyl-C(O)-O-, and R a R b N-aryloxy-.
  • alkyl-C(O)-O- or R a R b N-aryloxy- is optionally substituted with halo.
  • R 3 is -OH.
  • R 3 is alkyl-C(O)-O-.
  • R 3 is R a R b N-aryloxy-.
  • R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is R a R b N-aryloxy-. In some examples, R 3 is -NR a R b -aryloxy.
  • set forth herein is a compound of Formula ( PIa ), (PIb-1), (PIb-2), (PIc-1), (PIc-2), (PId-1), (PId-2), (PIe-1), or (PIe-2), wherein R 3 is R a R b N-aryloxy-, wherein R a and R b are, independently in each instance, H or alkyl.
  • set forth herein is a compound of Formula ( PIa ), (PIb-1), (PIb-2), (PIc-1), (PIc-2), (PId-1), (PId-2), (PIe-1), or (PIe-2), wherein R 4 is selected from the group consisting of alkyl, aryl, arylalkyl, and an N-containing heterocycloalkyl.
  • R 4 is selected from the group consisting of alkyl, aryl, arylalkyl, and an N-containing heterocycloalkyl.
  • alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl are optionally substituted with -NR a R b .
  • R 4 is alkyl such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. In some examples, R 4 is methyl. In some examples, R 4 is ethyl. In some examples, R 4 is n-propyl. In some examples, R 4 is i-propyl. In some examples, R 4 is n-butyl. In some examples, R 4 is i-butyl. In some examples, R 4 is t-butyl. In some examples, R 4 is pentyl. In some examples, R 4 is hexyl.
  • R 4 is heptyl. In some examples, R 4 is octyl, or nonyl. In some examples, R 4 is aryl such as but not limited to phenyl or naphthyl. In some examples, R 4 is phenyl. In some examples, R 4 is naphthyl. In some examples, R 4 is arylalkyl-such as but not limited to benzyl. In some examples, R 4 is N-containing heterocycloalkyl such as but not limited to piperidinyl. In some examples, R 4 is 4-amino-phenyl. In some examples, R 4 is 4-aminophenyl optionally substituted with halo.
  • R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is in some examples, R 4 is
  • R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is in some examples, R 4 is
  • R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is in some examples, R 4 is
  • R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is in some examples, R 4 is
  • R 4 is alkyl substituted with amino such as, but not limited to, methyl-amino, ethyl-amino, propyl-amino, butyl-amino, pentyl-amino, hexyl-amino, heptyl-amino, octyl-amino, or nonyl-amino. In some examples, R 4 is methyl-amino.
  • R 4 is ethyl-amino. In some examples, R 4 is n-propyl-amino. In some examples, R 4 is i-propyl-amino. In some examples, R 4 is n-butyl-amino. In some examples, R 4 is i-butyl-amino. In some examples, R 4 is t-butyl-amino. In some examples, R 4 is pentyl-amino. In some examples, R 4 is hexyl-amino. In some examples, R 4 is heptyl-amino. In some examples, R 4 is octyl-amino. In some examples, R 4 is nonyl-amino.
  • R 4 is In some examples, R 4 is . In some examples, R 4 is
  • the compound of Formula (I) is not one of the following compounds:
  • R 3 is selected from -OH, alkyl-C(O)-O-, or R a R b N-aryloxy. In some of these examples, alkyl-C(O)-O- or R a R b N-aryloxy is optionally substituted with halo. In some examples, R 3 is -OH. In some examples, R 3 is alkyl-C(O)-O-. In some examples, R 3 is R a R b N-aryloxy-. In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is R a R b N-aryloxy-.
  • R 4 is selected from the group consisting of alkyl, aryl, arylalkyl, and an N-containing heterocycloalkyl. In some of these examples, alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl are optionally substituted with -NR a R b .
  • R 4 is alkyl such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. In some examples, R 4 is methyl. In some examples, R 4 is ethyl.
  • R 4 is n-propyl. In some examples, R 4 is i-propyl. In some examples, R 4 is n-butyl. In some examples, R 4 is i-butyl. In some examples, R 4 is t-butyl. In some examples, R 4 is sec-butyl. In some examples, R 4 is pentyl. In some examples, R 4 is hexyl. In some examples, R 4 is heptyl. In some examples, R 4 is octyl, or nonyl. In some examples, R 4 is aryl such as but not limited to phenyl or naphthyl. In some examples, R 4 is phenyl. In some examples, R 4 is naphthyl.
  • R 4 is arylalkyl-such as but not limited to benzyl. In some examples, R 4 is N-containing heterocycloalkyl such as but not limited to piperidinyl. In some examples, R 4 is 4-amino-phenyl. In some examples, R 4 is 4-aminophenyl optionally substituted with halo.
  • R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is in some examples, R 4 is
  • R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is in some examples, R 4 is
  • R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is in some examples, R 4 is
  • R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is in some examples, R 4 is
  • R 4 is alkyl substituted with amino such as, but not limited to, methyl-amino, ethyl-amino, propyl-amino, butyl-amino, pentyl-amino, hexyl-amino, heptyl-amino, octyl-amino, or nonyl-amino.
  • R 4 is methyl-amino.
  • R 4 is ethyl-amino.
  • R 4 is n-propyl-amino.
  • R 4 is i-propyl-amino.
  • R 4 is n-butyl-amino.
  • R 4 is i-butyl-amino. In some examples, R 4 is t-butyl-amino. In some examples, R 4 is pentyl-amino. In some examples, R 4 is hexyl-amino. In some examples, R 4 is heptyl-amino. In some examples, R 4 is octyl-amino. In some examples, R 4 is nonyl-amino.
  • R 4 is In some examples, R 4 is . In some examples, R 4 is
  • R and R b are, independently in each instance, selected from H or alkyl. In some examples, both R a and R b are -H. In some examples, both R a and R b are methyl. In some examples, both R a and R b are ethyl. In some examples, both R a and R b are propyl. In some examples, one of R a or R b is -H and the other is alkyl. In some examples, one of R a or R b is -H and the other is methyl. In some examples, one of R a or R b is -H and the other is ethyl. In some examples, one of R a or R b is -H and the other is propyl.
  • n is an integer from 0-19. In some examples, n is 0. In some other examples, n is 1. In certain examples, n is 2. In some other examples, n is 3. In certain examples, n is 4. In some examples, n is 5. In some other examples, n is 6. In certain examples, n is 7. In some other examples, n is 8. In certain examples, n is 9. In some examples, n is 10. In some other examples, n is 11. In certain examples, n is 12. In some other examples, n is 13. In certain examples, n is 14. In some examples, n is 15. In some other examples, n is 16. In certain examples, n is 17. In some other examples, n is 18. In certain examples, n is 19.
  • R 4 is selected from 4-amino-phenyl, 4-amino-1-methyl-phenyl, 2-amino-ethyl, piperidinyl, or propyl.
  • R 4 is 4-amino-phenyl.
  • R 4 is 4-amino-1-methyl-phenyl.
  • R 4 is 2-amino-ethyl.
  • R 4 is piperidinyl.
  • R 4 is propyl.
  • R 4 is n-propyl.
  • R 4 is i-propyl.
  • set forth herein is a compound of Formula (PIIa) or (PIIb), wherein R 3 is selected from alkyl-C(O)-O- or R a R b N-aryloxy; wherein alkyl-C(O)-O-, or R a R b N-aryloxy are optionally substituted with halo.
  • set forth herein is a compound of Formula (PIIa) or (PIIb), wherein R 3 is
  • set forth herein is a compound of Formula (PIIa) or (PIIb), wherein R 3 is
  • set forth herein is a compound of Formula ( PIIa ) or ( PIIb ), wherein R 3 is
  • set forth herein is a compound of Formula ( PIIa ) or ( PIIb ), wherein the compound has the structure of Formula ( PIII ):
  • R 9 is selected from H or -NR a R b .
  • R 9 is H.
  • R 9 is -NR a R b , R 4 , R 4 , and subscript n are defined as in Formula I and noted above.
  • R 10 and R 11 are each, independently in each instance, selected from H, F, or -NR a R b .
  • set forth herein is a compound of Formula ( III ), wherein the compound has the structure of Formula ( PIIIa ) or ( PIIIb ):
  • PIV the structure of Formula (PIV):
  • -NR a R b , R 4 , R 5 , and subscript n are defined as in Formula I and noted above.
  • a compound of Formula (I) wherein the compound has the structure of Formula ( PV ):
  • R 4 , R 4 , and subscript n are defined as in Formula I and noted above.
  • set forth herein is a compound of Formula ( PV ), wherein the compound has the structure of Formula ( PVa ) or ( PVb ):
  • R 3 is selected from alkyl-C(O)-O- or R a R b N-aryloxy, wherein alkyl-C(O)-O-, or -NR a R b -aryloxy are optionally substituted with halo.
  • R 4 is selected from -H, -OH, halo, or alkyl.
  • R 4 is halo such as but not limited to -F, -Cl, -Br, or -I.
  • R 4 is -F.
  • R 4 is- Cl.
  • R 4 is -Br.
  • R 4 is -I.
  • R 4 is alkyl such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl.
  • Subscript n is an integer from 0-19.
  • n is 0. In some other examples, n is 1. In certain examples, n is 2. In some other examples, n is 3. In certain examples, n is 4. In some examples, n is 5. In some other examples, n is 6. In certain examples, n is 7. In some other examples, n is 8. In certain examples, n is 9. In some examples, n is 10. In some other examples, n is 11. In certain examples, n is 12. In some other examples, n is 13. In certain examples, n is 14. In some examples, n is 15. In some other examples, n is 16. In certain examples, n is 17. In some other examples, n is 18. In certain examples, n is 19.
  • R 3 is selected from -OH, alkyl-C(O)-O-, -NR a R b , or NR a R b -aryloxy. In some of these examples, alkyl-C(O)-O- or R a R b N-aryloxy is optionally substituted with halo. In some examples, R 3 is -OH. In some examples, R 3 is alkyl-C(O)-O-. In some examples, R 3 is R a R b N-aryloxy.
  • R 3 is -NR a R b . In some examples, R 3 is -NH 2 . In some examples, R 3 is -NH(CH 3 ).
  • R 3 is R a R b N-aryloxy.
  • R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is in some examples, R 3 is
  • R 3 is selected from alkyl-C(O)-O- or R a R b N-aryloxy, wherein alkyl-C(O)-O-, or R a R b N-aryloxy are optionally substituted with halo.
  • R 4 is selected from -H, -OH, halo, or alkyl.
  • R 4 is halo such as but not limited to -F, -Cl, -Br, or -I.
  • R 4 is -F.
  • R 4 is -Cl.
  • R 4 is -Br.
  • R 4 is -I.
  • R 4 is alkyl such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl.
  • Subscript n is an integer from 0-19.
  • n is 0. In some other examples, n is 1. In certain examples, n is 2. In some other examples, n is 3. In certain examples, n is 4. In some examples, n is 5. In some other examples, n is 6. In certain examples, n is 7. In some other examples, n is 8. In certain examples, n is 9. In some examples, n is 10. In some other examples, n is 11. In certain examples, n is 12. In some other examples, n is 13. In certain examples, n is 14. In some examples, n is 15. In some other examples, n is 16. In certain examples, n is 17. In some other examples, n is 18. In certain examples, n is 19.
  • R 3 is selected from -OH, alkyl-C(O)-O-, -NR a R b , or R a R b N-aryloxy. In some of these examples, alkyl-C(O)-O- or NR a R b -aryloxy is optionally substituted with halo. In some examples, R 3 is -OH. In some examples, R 3 is alkyl-C(O)-O-. In some examples, R 3 is R a R b N-aryloxy.
  • R 3 is -NR a R b . In some examples, R 3 is -NH 2 . In some examples, R 3 is -NH(CH 3 ).
  • R 3 is R a R b N-aryloxy-.
  • R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is in some examples, R 3 is
  • set forth herein is a compound of Formula ( PVII ), ( PVIIa ), or ( PVIIb ), wherein R 3 is or R a R b N-aryloxy- optionally substituted with halo.
  • set forth herein is a compound of Formula ( PVII ), ( PVIIa ), or ( PVIIb ), wherein R 3 is
  • set forth herein is a compound of Formula ( PVII ), ( PVIIa ), or ( PVIIb ), wherein R 3 is
  • set forth herein is a compound of Formula ( PVII ), wherein the compound has the structure of Formula ( PVIIb-1 ) or ( PVIIb-2 ):
  • set forth herein is a compound of Formula ( PVII ), ( PVIIa ), ( PVIIb ), ( PVIIb-1 ), or ( PVIIb-2 ), wherein R 3 is alkyl-C(O)-O- or R a R b N-aryloxy.
  • R 1 and R 2 are, independently, selected from -H, alkyl, alkyl-C(O)-O-, -OH, or halo. In some other examples, R 1 and R 2 together form In certain examples, R 1 is -H. In certain other examples, R 1 is alkyl. In some examples, R 1 is alkyl-C(O)-O-. In some other examples, R 1 is -OH. In certain examples, R 1 is halo. In certain other examples, R 1 is -F. In some examples, R 1 is -Cl. In some other examples, R 1 is -Br. In certain examples, R 1 is -I. In certain other examples, R 2 is -OH. In some examples, R 2 is halo. In some other examples, R 2 is -F. In certain examples, R 2 is -Cl. In certain other examples, R 2 is -Br. In some examples, R 2 is -I. In certain other examples, R 2 is -OH. In some examples, R 2
  • R 5 is, independently in each instance, selected from -OH, halo, alkyl, or arylalkyl.
  • R 5 is -OH.
  • R 5 is halo such as but not limited to -F, -Cl, -Br, or -I.
  • R 5 is -F.
  • R 5 is -Cl.
  • R 5 is -Br.
  • R 5 is -I.
  • R 5 is alkyl such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. In some examples, R 5 is benzyl.
  • R 4 is selected from the group consisting of alkyl, aryl, arylalkyl, and an N-containing heterocycloalkyl. In some of these examples, alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl are optionally substituted with -NR a R b .
  • R 4 is alkyl such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. In some examples, R 4 is methyl. In some examples, R 4 is ethyl.
  • R 4 is n-propyl. In some examples, R 4 is i-propyl. In some examples, R 4 is n-butyl. In some examples, R 4 is i-butyl. In some examples, R 4 is t-butyl. In some examples, R 4 is sec-butyl. In some examples, R 4 is pentyl. In some examples, R 4 is hexyl. In some examples, R 4 is heptyl. In some examples, R 4 is octyl, or nonyl. In some examples, R 4 is aryl such as but not limited to phenyl or naphthyl. In some examples, R 4 is phenyl. In some examples, R 4 is naphthyl.
  • R 4 is arylalkyl-such as but not limited to benzyl. In some examples, R 4 is N-containing heterocycloalkyl such as but not limited to piperidinyl. In some examples, R 4 is 4-amino-phenyl. In some examples, R 4 is 4-aminophenyl optionally substituted with halo.
  • R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is in some examples, R 4 is
  • R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is In some examples, R 4 is in some examples, R 4 is
  • R 4 is alkyl substituted with amino such as, but not limited to, methyl-amino, ethyl-amino, propyl-amino, butyl-amino, pentyl-amino, hexyl-amino, heptyl-amino, octyl-amino, or nonyl-amino.
  • R 4 is methyl-amino.
  • R 4 is ethyl-amino.
  • R 4 is n-propyl-amino.
  • R 4 is i-propyl-amino.
  • R 4 is n-butyl-amino.
  • R 4 is i-butyl-amino. In some examples, R 4 is t-butyl-amino. In some examples, R 4 is sec-butyl. In some examples, R 4 is pentyl-amino. In some examples, R 4 is hexyl-amino. In some examples, R 4 is heptyl-amino. In some examples, R 4 is octyl-amino. In some examples, R 4 is nonyl-amino.
  • R 4 is In some examples, R 4 is . In some examples, R 4 is
  • R a and R b are, independently in each instance, selected from H or alkyl. In some examples, both R a and R b are H. In some examples, both R a and R b are methyl. In some examples, both R a and R b are ethyl. In some examples, both R a and R b are propyl. In some examples, one of R a or R b is H and the other is alkyl. In some examples, one of R a or R b is H and the other is methyl. In some examples, one of R a or R b is H and the other is ethyl. In some examples, one of R a or R b is H and the other is propyl.
  • n is an integer from 0-19. In some examples, n is 0. In some other examples, n is 1. In certain examples, n is 2. In some other examples, n is 3. In certain examples, n is 4. In some examples, n is 5. In some other examples, n is 6. In certain examples, n is 7. In some other examples, n is 8. In certain examples, n is 9. In some examples, n is 10. In some other examples, n is 11. In certain examples, n is 12. In some other examples, n is 13. In certain examples, n is 14. In some examples, n is 15. In some other examples, n is 16. In certain examples, n is 17. In some other examples, n is 18. In certain examples, n is 19.
  • R 3 is not -OH when R 1 is -OH.
  • R 3 is not -OH when R 1 and R 2 together form wherein R 4 is a C 1-9 alkyl or 4-(dimethyl-amino)-phenyl.
  • R 4 is alkyl, aryl, arylalkyl, or a N-containing heterocycloalkyl.
  • alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl are optionally substituted with -NR a R b .
  • R 4 is alkyl.
  • R 4 is aryl.
  • R 4 is arylalkyl.
  • R 4 is N-containing heterocycloalkyl.
  • R 4 is alkyl such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. In some examples, R 4 is methyl. In some examples, R 4 is ethyl. In some examples, R 4 is n-propyl. In some examples, R 4 is i-propyl. In some examples, R 4 is n-butyl. In some examples, R 4 is i-butyl. In some examples, R 4 is t-butyl. In some examples, R 4 is sec-butyl. In some examples, R 4 is pentyl.
  • R 4 is hexyl. In some examples, R 4 is heptyl. In some examples, R 4 is octyl. In some examples, R 4 is nonyl. In some examples, R 4 is aryl such as but not limited to phenyl or naphthyl. In some examples, R 4 is phenyl. In some examples, R 4 is naphthyl. In some examples, R 4 is arylalkyl-such as but not limited to benzyl. In some examples, R 4 is N-containing heterocycloalkyl such as but not limited to piperidinyl. In some examples, R 4 is 4-amino-phenyl. In some examples, R 4 is 4-aminophenyl optionally substituted with halo.
  • R 1 and R 2 together form wherein R 4 is selected from the group consisting of alkyl, aryl, arylalkyl, and a N-containing heterocycloalkyl; and wherein alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl are optionally substituted with -NR a R b ; and wherein the stereochemistry of the carbon indicated by * is R.
  • R 1 and R 2 together form wherein R 4 is selected from the group consisting of alkyl, aryl, arylalkyl, and a N-containing heterocycloalkyl; and wherein alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl are optionally substituted with -NR a R b ; and wherein the stereochemistry of the carbon indicated by * is S.
  • R 3 is not -OH when R 1 is -OH or when R 1 and R 2 together form wherein R 4 is a C 1-9 alkyl or 4-(dimethyl-amino)-phenyl.
  • the payload set forth herein is a derivative or analog of budesonide or diflorasone.
  • the derivative is an amine or aniline containing molecule which is related in structure to budesonide or diflorasone.
  • the payloads set forth herein as well as other steroids can be conjugated to an antibody or an antigen-binding fragment thereof based on the methods set forth herein.
  • the payloads set forth herein as well as other steroids can be conjugated to an antibody, or an antigen-binding fragment thereof, and also to a cyclodextrin moiety based on the methods set forth herein.
  • stable linker-payloads can be use with these methods of conjugation to produce antibody-steroid-conjugates.
  • the antibody-steroid conjugates also include a cyclodextrin moiety.
  • alkyl-C(O)-O- or -X-aryl-NR a R b is optionally substituted with halo.
  • R 3 is -OH.
  • R 3 is alkyl-C(O)-O-.
  • R 3 is R a R b N-aryloxy.
  • R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is o
  • R 3 is -X-aryl-NR a R b .
  • R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is in some examples, R 3 is
  • R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is in some examples, R 3 is
  • R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is in some examples, R 3 is
  • R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is in some examples, R 3 is
  • R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is in some examples, R 3 is
  • R 3 has a structure selected from one of the following structures:
  • R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In these examples, q is an integer from 0 to 5.
  • R 3 has a structure selected from one of the following structures:
  • R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In these examples, q is an integer from 0 to 5.
  • R 3 has a structure selected from one of the following structures: In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is
  • R 1 and R 2 are, independently, selected from the group consisting of -H, -OH, alkyl, -O-C(O)-alkyl, and halo; or R 1 and R 2 together form wherein R 4 is selected from the group consisting of alkyl, aryl, alkylaryl, arylalkyl, heteroaryl, -alkylene-NR a R b , -X-arylene-Y-NR a R b , -X-heteroarylene-Y-NR a R b , and N-containing heterocycloalkyl; wherein X is absent, -N-, -CH 2 -, or -O-; wherein Y is absent or -CH 2 -.
  • R 3 is selected from the group consisting of -OH, -O-C(O)-alkyl, -O-aryl, -NR a R b , -alkylene-NR a R b , -X-arylene-Y-NR a R b , -X-heteroarylene-Y-NR a R b , and N-containing heterocycloalkyl; wherein X is absent, -N-, -CH 2 -, or -O-; wherein Y is absent or -CH 2 -.
  • R 5 is, independently in each instance, selected from a substituent in the group consisting of -OH, halo, and alkyl; n is an integer from 0-19; and each R 5 is positioned on any ring atom.
  • R a and R b are, independently in each instance, selected from the group consisting of -H and alkyl; or R a and R b cyclize to form cycloheteroalkyl with three to six ring atoms, including one hetero atom, which is the N to which they are attached.
  • R a and R b are, independently in each instance, optionally substituted with at least one substituent selected from the group consisting of -OH, -PO 4 H, NH 2 , -C(O)OH, and -C(O)CH 3 .
  • R 3 is selected from the group consisting of -alkylene-NR a R b , -X-arylene-Y-NR a R b , -X-heteroarylene-Y-NR a R b , and N-containing heterocycloalkyl; wherein X is absent, -N-, -CH 2 -, or -O-; wherein Y is absent or -CH 2 -; and R 4 is selected from the group consisting of alkyl, aryl, alkylaryl, arylalkyl, heteroaryl, -alkylene-NR a R b , -X-arylene-Y-NR a R b , -X-heteroarylene-Y-NR a R b , and N-containing heterocycloalkyl; wherein X is absent, -N-, -CH 2 -, or -O-; wherein
  • R 3 is selected from the group consisting of -OH, -O-C(O)-alkyl, -O-aryl, -NR a R b , -alkylene-NR a R b , -X-arylene-Y-NR a R b , -X-heteroarylene-Y-NR a R b , and N-containing heterocycloalkyl; wherein X is absent, -N-, -CH 2 -, or -O-; wherein Y is absent or -CH 2 -; and R 4 is selected from the group consisting of -alkylene-NR a R b , -X-arylene-Y-NR a R b , -X-heteroarylene-Y-NR a R b , and N-containing heterocycloalkyl; wherein X is absent, -N-, -CH 2 -
  • R 3 is -NR a R b ; and R 4 is alkyl.
  • R 3 is -NH 2 .
  • R 4 is n-propyl.
  • R 3 is -NH 2 and R 4 is n-propyl.
  • the compound of Formula 1000 is according to Formula 1010, 1020, 1030, or 1040: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the compound of Formula 1000 is according to Formula 1110, 1120, 1130, or 1140: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • R 3 is -OH or -O-C(O)-alkyl
  • R 4 is -alkylene-NR a R b , -X-arylene-NR a R b , -X-heteroarylene-NR a R b , or N-containing heterocycloalkyl; wherein X is absent or -CH 2 -.
  • R 4 is -alkylene-NH 2 , -C 6 H 5 -NH 2 or -CH 2 -C 6 H 5 -NH 2 .
  • R 3 is -O-aryl, -NR a R b , -alkylene-NR a R b , -X-arylene-Y-NR a R b , -X-heteroarylene-Y-NR a R b , or N-containing heterocycloalkyl; wherein X is absent, -N-, -CH 2 -, or -O-; wherein Y is absent or -CH 2 -; and R 4 is alkyl, aryl, alkylaryl, or arylalkyl.
  • R 3 is -O-arylene-NR a R b , -O-heteroarylene-NR a R b ; wherein aryl or heteroaryl is optionally substituted with halogen, deuterium, hydroxyl, or methoxyl.
  • R 3 is -O-phenyl-NR a R b , -O-heteroarylene-NR a R b ; wherein phenyl or heteroaryl is optionally substituted with halogen or deuterium.
  • R 4 is n-propyl.
  • R 3 is -NR a R b ; and R 4 is alkyl.
  • R 3 is -NH 2 .
  • R 4 is n-propyl.
  • R 3 is -NH 2 and R 4 is n-propyl.
  • R 3 can be any specific R 3 provided above.
  • R 3 is -NH 2 , -N(H)CH 3 , -N(CH 3 ) 2 , or In particular embodiments, R 3 is In particular embodiments, R 3 is In particular embodiments, R 3 is In particular embodiments, R 3 is
  • R 4 can be any specific R 4 provided above.
  • R 4 is selected from -CH 2 -CH 2 -NH 2 , In particular embodiments, R 4 is n-propyl.
  • conjugates of the steroids described herein include proteins, e.g ., antibodies or antigen-binding fragments thereof, that are covalently linked, e.g ., via the binding agent linkers described herein, to the compounds described in Section B above, e.g., the compounds of Formula ( A ), ( A 1 ), ( A 2 ), ( A 3 ), ( A 4 ), ( A 5 ), ( A 6 ), (A 7 ), ( I ), ( I 1 ), ( PIa ), ( PIb-1 ), ( PIb-2 ), PIc-1 ), ( PIc-2 ), ( PId-1 ), ( PId-2 ), ( PIe-1 ), ( PIe-2 ), ( PIII ), ( PIIa ), ( PIIb ), ( PIII ), ( PIIIa ), ( PIIIb ), ( PIV ), ( PV ), ( PVa ), ( PVb ), ( PVI ), ( PVI ), ( PVI ), (
  • the binding agent linker can be linked to a steroid described herein at any suitable moiety or position of the steroid, including e.g., through an amide, ether, ester, carbamate, or amine.
  • the binding agent linker can be attached to compounds through R 1 , R 3 , or R 4 or hydroxyl group depicted Formula ( A 1 ):
  • the steroids described herein are attached to the binding agent linker by reacting an amino or hydroxyl group of the steroid with a suitable reactive group present on the linker.
  • the binding agent linker also includes a cyclodextrin moiety.
  • the cyclodextrin moiety may be bonded to the chemical backbone structure of the binding agent linker.
  • BA-(L-PAY) x wherien BA is a binding agent as described herein; L is an optional linker as described herein; PAY is a steroid compound as described herein; and x is an integer from 1-30.
  • each PAY is a radical obtainable by removal of an atom, for example a hydrogen atom from a compound according to a Formula selected from the group consisting of Formulas ( A ), ( A 1 ), ( A 2 ), ( A 3 ), ( A 4 ), ( A 5 ), ( A 6 ), ( A 7 ), ( I ), ( I 1 ), ( PIa ), ( PIb-1 ), ( PIb-2 ), PIc-1 ), ( PIc-2 ), ( PId-1 ), ( PId-2 ), ( PIe-1 ), ( PIe-2 ), ( PII ), ( PIIa ), ( PIIb ), ( PIII ), ( PIIIa ), ( PIIIb ), ( PIV ), ( PV ), ( PVa ), ( PVb ), ( PVI ), ( PVII ), ( PVIIa ), ( PVIIb ), ( PVIIb-1 ), ( PVIIb-2 ), ( PVIII
  • subscript x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In some examples, subscript x is 0. In some examples, subscript x is 1. In some examples, subscript x is 2. In some examples, subscript x is 3. In some examples, subscript x is 4. In some examples, subscript x is 5. In some examples, subscript x is 6. In some examples, subscript x is 7. In some examples, subscript x is 8. In some examples, subscript x is 9. In some examples, subscript x is 10. In some examples, subscript x is 11. In some examples, subscript x is 12. In some examples, subscript x is 13. In some examples, subscript x is 14.
  • subscript x is 15. In some examples, subscript x is 16. In some examples, subscript x is 17. In some examples, subscript x is 18. In some examples, subscript x is 19. In some examples, subscript x is 20. In some examples, subscript x is 21. In some examples, subscript x is 22. In some examples, subscript x is 23. In some examples, subscript x is 24. In some examples, subscript x is 25. In some examples, subscript x is 26. In some examples, subscript x is 27. In some examples, subscript x is 28. In some examples, subscript x is 29. In some examples, subscript x is 30.
  • R 1 and R 2 are, each, independently, -H, alkyl, or -OH. In some examples of Formula ( III ), one of R 1 or R 2 is -H, alkyl, or -OH. In some examples of Formula ( III ), both R 1 and R 2 are either -H, alkyl, or -OH.
  • R 1 and R 2 together form
  • R 4 is -RL.
  • R 4 is RL-NR a -aryl.
  • R 4 is alkyl.
  • R 4 is arylalkyl,
  • R 4 is aryl.
  • R 4 is N-containing heterocycloalkyl.
  • the alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl is optionally substituted.
  • R 5 is -H or halo. In some examples of Formula ( II ), R 5 is -H or fluoro. In some examples of Formula ( III ), one of R 5 is -H or halo. In some examples of Formula ( III ), R 5 is -H or halo and n is 2. In some examples of Formula ( III ), R 5 is -F and n is 1. In some examples of Formula ( II ), R 5 is -F and n is 2.
  • R 3 is BL. In some examples of Formula ( III ), R 3 is RL -NR a -aryloxy-. In some other examples of Formula ( III ), R 3 is -OH. In some other examples of Formula ( III ), R 3 is alkyl-C(O)-O-. In some other examples of Formula ( III ), R 3 is heteroalkyl. In some other examples of Formula ( III ), R 3 is -N-R a R b . In some other examples of Formula ( III ), R 3 is aryl. In some other examples of Formula ( III ), R 3 is aryloxy.
  • alkyl-C(O)-O-, heteroalkyl, or aryloxy is optionally substituted with -NR a R b or halo.
  • R 3 is -OH.
  • R 3 is alkyl-C(O)-O-.
  • R 3 is In some examples of Formula ( III ), R 3 is heteroalkyl.
  • R 3 is In some examples of Formula ( III ), R 3 is In some examples of Formula ( III ), R 3 is -NR a R b . In some examples, R 3 is -NR a R b -aryloxy.
  • R 3 is In some examples R 3 is In some examples, R 3 is In some examples, R 3 is In some examples R 3 is aryloxy. In some examples R 3 is In some examples R 3 is In some examples R 3 is In some examples, R 3 is In some examples R 3 is In some examples R 3 is In some examples R 3 is In some examples R 3 is In some examples R 3 is In some examples R 3 is In some examples R 3 is In some examples R 3 is In some examples R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is In some examples, R 3 is aryloxy. In some examples R 3 is In some examples R 3 is In some examples R 3 is In some examples R 3 is In some examples R 3 is In some examples R 3 is In some examples R 3 is In some examples R 3 is In some examples R 3 is In some examples, R 3 is aryloxy. In some examples R 3 is In some examples R 3 is In some examples R 3 is In some examples R 3 is In some examples R
  • n is an integer from 0-19. In some examples, n is 0. In some other examples, n is 1. In certain examples, n is 2. In some other examples, n is 3. In certain examples, n is 4. In some examples, n is 5. In some other examples, n is 6. In certain examples, n is 7. In some other examples, n is 8. In certain examples, n is 9. In some examples, n is 10. In some other examples, n is 11. In certain examples, n is 12. In some other examples, n is 13. In certain examples, n is 14. In some examples, n is 15. In some other examples, n is 16. In certain examples, n is 17. In some other examples, n is 18. In certain examples, n is 19.
  • the compound of Formula ( IIIa2 ) has the following structure: wherein:
  • R 5 is -H or halo. In some examples of Formula ( IIIb ), R 5 is fluoro. In some examples of Formula ( IIIb ), n is at least 2, and two of R 5 is halo. In some examples of Formula ( IIIb ), R 5 is -F and n is 1. In some examples of Formula ( IIIb ), R 5 is -F.
  • R 4 is alkyl.
  • R 4 is methyl, ethyl, n -propyl, i -propyl, n -butyl, s -butyl, t -butyl, i -butyl, a pentyl moiety, a hexyl moiety, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 4 is n -propyl.
  • the compound of Formula ( IIIb ) has the following structure: wherein:
  • R 5 is halo. In some examples of Formula ( IIIc ), R 5 is fluoro. In some examples of Formula ( IIIc ), one of R 5 is halo. In some examples of Formula ( IIIc ), two of R 5 is halo. In some examples of Formula ( IIIc ), R 5 is -F and n is 2.
  • R 1 is CH 3 .
  • R 1 is OH.
  • R 1 is H.
  • R 2 is CH 3 .
  • R 2 is OH.
  • R 2 is H.
  • R 1 is CH 3 and R 2 is CH 3 .
  • R 1 is CH 3 and R 2 is OH.
  • R 1 is CH 3 and R 2 is H.
  • R 1 is OH and R 2 is CH 3 .
  • R 1 is OH and R 2 is OH.
  • R 1 is H and R 2 is H.
  • R 1 is H and R 2 is OH.
  • R 1 is H and R 2 is H.
  • the compound of Formula ( IIIc ) has the following structure: wherein:
  • the compound of Formula ( IIIc ) has the following structure:
  • n is an integer from 0 to 4
  • R 3 is -OH or R Z -C(O)-O-; wherein R Z is alkyl, BL is a binding agent linker, BA is a binding agent, and x is an integer from 1 to 30.
  • n is 0 or 1 and x is an integer from 1-6. In certain embodiments, x is 4.
  • n is an integer from 1-4, R 3 is -OH or R Z -C(O)-O-; wherein R Z is alkyl, BL is a binding agent linker, BA is a binding agent, and x is an integer from 1-30. In certain embodiments, n is 2 and x is an integer from 1-6. In certain embodiments, x is 4.
  • R 4 is alkyl, wherein R a is a hydrogen atom or alkyl, BL is a binding agent linker, and BA is a binding agent.
  • R 4 is C 1-4 alkyl.
  • R 4 is propyl.
  • R 3 is -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 .
  • x is an integer from 1-6. In certain embodiments, x is 4.
  • R 4 is alkyl
  • R P1 is halo or a hydrogen atom
  • X is NR a or O
  • R a is a hydrogen atom or alkyl
  • BL is a binding agent linker
  • BA is a binding agent
  • x is an integer from 1-30.
  • R 4 is C 1-4 alkyl
  • X is NH
  • x is an integer from 1-6.
  • x is 4.
  • X is O or NRa
  • A is aryl or heteroaryl
  • R P is halo
  • t is an integer from 0-2
  • R a is a hydrogen atom or alkyl
  • BL is a binding agent linker
  • BA is a binding agent
  • x is an integer from 1-30
  • R 4 is alkyl.
  • X is O
  • R 4 is alkyl
  • x is an integer from 1-6.
  • x is 4.
  • Ra is a hydrogen atom or alkyl
  • BL is a binding agent linker
  • BA is a binding agent
  • x is an integer from 1-30. In some embodiments, x is an integer from 1-6. In some embodiments, x is 4.
  • binding agent linker refers to any divalent group or moiety that links, connects, or bonds a binding agent (e.g., an antibody or an antigen-binding fragment thereof) with a payload compound set forth herein (e.g. , steroid).
  • a binding agent e.g., an antibody or an antigen-binding fragment thereof
  • a payload compound set forth herein e.g. , steroid
  • suitable binding agent linkers for the antibody conjugates described herein are those that are sufficiently stable to exploit the circulating half-life of the antibody and, at the same time, capable of releasing its payload after antigen-mediated internalization of the conjugate. Linkers can be cleavable or non-cleavable.
  • Cleavable linkers are linkers that are cleaved by intracellular metabolism following internalization, e.g., cleavage via hydrolysis, reduction, or enzymatic reaction.
  • Non-cleavable linkers are linkers that release an attached payload via lysosomal degradation of the antibody following internalization.
  • Suitable linkers include, but are not limited to, acid-labile linkers, hydrolysis-labile linkers, enzymatically cleavable linkers, reduction labile linkers, self-immolative linkers, and non-cleavable linkers.
  • Suitable linkers also include, but are not limited to, those that are or comprise glucuronides, succinimide-thioethers, polyethylene glycol (PEG) units, carbamates, hydrazones, malcaproyl units, disulfide units (e.g.
  • R 1 and R 2 are independently hydrogen or hydrocarbyl), para-amino-benzyl (PAB) units, phosphate units, e.g., mono-, bis-, and tris- phosphate units, peptides, e.g., peptide units containing two, three, four, five, six, seven, eight, or more amino acid units, including but not limited to valine-citrulline units, valine-alanine units, valine-arginine units, valine-lysine units, -lysine-valine-citrulline units, and -lysine-valine-alanine units.
  • PAB para-amino-benzyl
  • the binding agent linker group of the conjugates described herein are derived from the reaction of a "reactive linker” group of a linker-payload described herein with a reactive portion of an antibody.
  • the reactive linker group refers to a monovalent group that comprises a reactive group and linking group, depicted as wherein RG is the reactive group, L is the linking group, and the wiggly line represents a bond to a payload.
  • the linking group is any divalent moiety that bridges the reactive group to the payload.
  • the linking group may also be any trivalent moiety that bridges the reactive group, the payload and a cyclodextrin moiety.
  • the linking group is trivalent and includes a cyclodextrin moiety bonded to a trivalent group (e.g., a lysine residue) in the linking group.
  • the reactive linkers (RL), together with the payloads to which they are bonded, comprise intermediates ("linker-payloads") useful as synthetic precursors for the preparation of the antibody steroid conjugates described herein.
  • the reactive linker contains a reactive group (RG), which is a functional group or moiety that reacts with a reactive portion of an antibody, modified antibody, or antigen binding fragment thereof.
  • BL binding agent linker
  • RG N is derived from the reaction of RG with a cysteine or lysine residue of an antibody or antigen-binding fragment thereof. In certain embodiments, RG N is derived from a click chemistry reaction. In some embodiments of said click chemistry reaction, RG N is derived from a 1,3 cycloaddition reaction between an alkyne and an azide.
  • Non-limiting examples of such RG N s include those derived from strained alkynes, e.g., those suitable for strain-promoted alkyne-azide cycloadditions (SPAAC), cycloalkynes, e.g ., cyclooctynes, benzannulated alkynes, and alkynes capable of undergoing 1,3 cycloaddition reactions with azides in the absence of copper catalysts.
  • Suitable RG N s also include, but are not limited to those derived from DIBAC, DIBO, BARAC, substituted, e.g ., fluorinated alkynes, aza-cycloalkynes, BCN, and derivatives thereof.
  • Conjugates containing such RG N groups can be derived from antibodies that have been functionalized with azido groups.
  • Such functionalized antibodies include antibodies functionalized with azido-polyethylene glycol groups.
  • such functionalized antibody is derived by reacting an antibody comprising at least one glutamine residue with a compound according to the formula H 2 N-LL-N 3 , wherein LL is a divalent polyethylene glycol group, in the presence of the enzyme transglutaminase, e.g., microbial transglutaminase.
  • Suitable glutamine residues of an antibody include Q295, or those derived by insertion or mutation, e.g ., N297Q mutation.
  • BA of the conjugates described herein is an antibody or an antigen-binding fragment thereof. In some embodiments, the conjugates described herein are derived from azido-functionalized antibodies. In certain embodiments, BA of the conjugates described herein is: wherein Ab is an antibody or antigen-binding fragment thereof, n is an integer from 1 to 10, w is the number of linker payload moieties, and is a bond to a single binding agent linker (BL), e.g., bond to a moiety derived from a 1,3-cycloaddition reaction between an alkyne and azide. In certain embodiments, w is 3. In certain embodiments, w is 2 or 4, i.e., the conjugate comprises 2 or 4 linker payload moieties.
  • BL is a divalent moiety of Formula ( BL A ); -RG N -(SP 1 ) q -(A) z -(NR a ) s -(B) t -(CH 2 ) u -(O) v -(SP 2 ) w - ( BL A );
  • BL is a trivalent moiety of Formula ( BL B ); -RG N -(SP 1 ) q -(A) r -(NR a ) s -(B) t -(CH 2 ) u -(O) v -( SP 2 ) w - ( BL B );
  • the cyclodextrin (CD) is bonded directly to an amino acid residue, such as a lysine amino acid residue. This means that the CD is one bond position away from the lysine amino acid covalent linker.
  • the covalent linker is also bonded directly to a payload moiety. This means that the covalent linker is one bond position away from a payload such as, but not limited to a steroid payload set forth herein.
  • the covalent linker is also bonded directly to a CD moiety. This means that the covalent linker is one bond position away from a CD, such as the CD(s) set forth herein.
  • the covalent linker is a lysine amino acid or a derivative thereof.
  • the CD is bonded indirectly to a covalent linker in a linking group (e.g., a BL).
  • a linking group e.g., a BL
  • the CD is more than one bond position away from the covalent linker.
  • the CD is bonded through another moiety to the covalent linker.
  • the CD may be bonded to a maleimide group which is bonded to a polyethylene glycol group which is bonded to the covalent linker.
  • the covalent linker is also bonded indirectly to a payload moiety. This means that the covalent linker is more than one bond position away from a payload such as, but not limited to a steroid payload set forth herein.
  • the covalent linker is bonded through another moiety to the payload.
  • the covalent linker may be bonded to a dipeptide, such as but not limited to Val-Ala or Val-Cit, which may be bonded to para-amino benzoyl which may be bonded to the payload.
  • the covalent linker is also bonded indirectly to a cyclodextrin moiety. This means that the covalent linker is more than one bond position away from a cyclodextrin, such as the cyclodextrins set forth herein. This also means that the covalent linker is bonded through another moiety to the cyclodextrin.
  • the covalent linker may be bonded to a polyethylene glycol group which may be bonded to reactive group which may be bonded to the cyclodextrin.
  • the covalent linker is a lysine amino acid or a derivative thereof.
  • BL is -RG N -(SP 1 ) q -(A) z -. In some embodiments, BL is -RG N -(SP 1 ) q -(A) 2 -. In some embodiments, BL is a moiety of Formula ( BL A1 ) wherein R AA1 and R AA2 are each, independently, amino acid side chains. In some examples of Formula RL A1 , SP 1 is a divalent polyethylene glycol group and RG N is a 1,3-cycloaddition reaction adduct of the reaction between an alkyne and an azide.
  • BL is -RG N -(SP 1 ) q -(A) z -. In some embodiments, BL is -RG N -(SP 1 ) q -(A) 2 -. In some embodiments, BL is a moiety of Formula ( BL B1 ) wherein R AA1 and R AA2 are each, independently, amino acid side chains. R AA3 is an amino acid side chain that is bonded directly or indirectly to a cyclodextrin moiety. In some examples of Formula RL B1 , SP 1 is a divalent polyethylene glycol group and RG N is a 1,3-cycloaddition reaction adduct of the reaction between an alkyne and an azide.
  • BL has the following structure: -RG N -(SP 1 ) q -Z 1 -Z 2 -Z 3 0-1 - wherein:
  • the BL is attached to the payload via tertiary amine.
  • the RL can bond to the tertiary amine as follows:
  • RG N is derived from a click-chemistry reactive group. In some examples, RG N is: or mixture thereof; or or mixture thereof; wherein is a bonding to a binding agent.
  • RG N is selected from a group which reacts with a cysteine or lysine residue on an antibody or an antigen-binding fragment thereof.
  • RG N is wherein is a bond to cysteine of a binding agent, e.g., antibody.
  • RG N is
  • SP 1 is selected from: In some examples, SP 1 is In some other examples, SP 1 is In other examples, SP 1 is In still other examples, SP 1 is In some other examples, SP 1 is In any of the above examples, subscripts a, b, and c are independently, in each instance, an integer from 1 to 20.
  • R AA3 is selected from wherein CD is a cyclodextrin moiety. In some embodiments, R AA3 is selected from
  • SP 1 is selected from:
  • SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is
  • SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is
  • BL-SP 1 is: or mixture thereof; or mixture thereof; or mixture thereof; or in some of these examples, subscripts b, c, and d are independently, in each instance, an integer from 1 to 20.
  • BL-SP 1 is selected from: or mixture thereof; or mixture thereof; or
  • A is a peptide selected from valine-citrulline, citrulline-valine, lysine-phenylalanine, phenylalanine-lysine, valine-asparagine, asparagine-valine, threonine-asparagine, asparagine-threonine, serine-asparagine, asparagine-serine, phenylalanine-asparagine, asparagine-phenylalanine, leucine-asparagine, asparagine-leucine, isoleucine-asparagine, asparagine-isoleucine, glycine-asparagine, asparagine-glycine, glutamic acid-asparagine, asparagine-glutamic acid, citrulline-asparagine, asparagine-citrulline, alanine-asparagine, or asparagine-alanine.
  • A is valine-citrulline or citrulline-valine.
  • A is valine-alanine or alanine-valine.
  • A is lysine-valine-alanine or alanine-valine-lysine.
  • A is lysine-valine-citrulline or citrulline-valine-lysine.
  • A is valine.
  • A is alanine
  • A is citrulline
  • A is In some of these examples, R AA1 is an amino acid side chain, and wherein R AA2 is an amino acid side chain.
  • A is in some of these examples, R AA1 is an amino acid side chain, R AA2 is an amino acid side chain, and R AA3 is an amino acid side chain that is bonded directly or indirectly to a cyclodextrin moiety.
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is wherein CD represents a direct or indirect bond to a cyclodextrin moiety.
  • CD is, independently in each instance, selected from In some examples, the CD is In some examples, the CD is In some examples, the CD is In some examples, the CD is In some examples, the CD is In some examples, the CD is In some examples, the CD is in some examples, the CD is, the CD is
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R a is H
  • R a is alkyl
  • R a is methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, or pentyl.
  • B is aryl
  • B is phenyl
  • B is phenyl or pyridinyl.
  • B is:
  • R 10 is alkyl, alkenyl, alkynyl, alkoxy, aryl, alkylaryl, arylalkyl, halo, haloalkyl, haloalkoxy, heteroaryl, heterocycloalkyl, hydroxyl, cyano, nitro, - -OR A , - -SO 2 R A , NR a R b , or azido.
  • subscripts p and m are independently, in each instance, selected from an integer from 0 to 4.
  • B is: In these examples, p is 0, 1, 2, 3 or 4.
  • R 1 is, independently at each occurrence, alkyl, alkoxy, haloalkyl, or halo. In some examples, R 1 is alkyl. In some examples, R 1 is alkoxy. In some examples, R 1 is haloalkyl. In some examples, R 1 is halo.
  • the -(NR a ) s -(B) t -(CH 2 ) u -(O) v -( SP 2 ) w is:
  • antibody-steroid conjugates having the following formulas: or a pharmaceutically acceptable salt or solvate thereof; wherein BA is a binding agent, and x is an integer from 1-30.
  • BA is an antibody.
  • x is an integer from 1 to 4.
  • x is 4.
  • x is 2.
  • antibody-steroid conjugates according to Formula 1200: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: BA is a binding agent; each L is an optional linker; BA or L is covalently bonded to R 3 or R 4 ; and x is an integer from 1 to 30.
  • BA is an antibody.
  • x is an integer from 1 to 4.
  • x is 4.
  • x is 2.
  • R 1 and R 2 are, independently, selected from the group consisting of -H, -OH, alkyl, -O-C(O)-alkyl, and halo; or R 1 and R 2 together form
  • R 3 is selected from the group consisting of -alkylene-NR a R b , -X-arylene-Y-NR a R b , -X-heteroarylene-Y-NR a R b , and N-containing heterocycloalkyl; wherein X is absent, -N-, -CH 2 -, or -O-; wherein Y is absent or -CH 2 -; and R 4 is selected from the group consisting of alkyl, aryl, alkylaryl, arylalkyl, heteroaryl, -alkylene-NR a R b , -X-arylene-Y-NR a R b , -X-heteroarylene-
  • R 3 is selected from the group consisting of -OH, -O-C(O)-alkyl, -O-aryl, -NR a R b , -alkylene-NR a R b , -X-arylene-Y-NR a R b , -X-heteroarylene-Y-NR a R b , and N-containing heterocycloalkyl; wherein X is absent, -N-, -CH 2 -, or -O-; wherein Y is absent or -CH 2 -; and R 4 is selected from the group consisting of -alkylene-NR a R b , -X-arylene-Y-NR a R b , -X-heteroarylene-Y-NR a R b , and N-containing heterocycloalkyl; wherein X is absent, -N-, -CH 2 -, or -O-; wherein
  • R 3 is -NR a R b ; and R 4 is alkyl.
  • BA or L is bonded to a functional group in R 3 or R 4 .
  • R 3 or R 4 comprises a amino group
  • BA or L can be bonded to the amino group, substituting for a hydrogen atom.
  • R 5 is, independently in each instance, selected from a substituent in the group consisting of -OH, halo, and alkyl; n is an integer from 0-19; and each R 5 is positioned on any ring atom.
  • R a and R b are, independently in each instance, selected from the group consisting of -H and alkyl; or R a and R b cyclize to form cycloheteroalkyl with three to six ring atoms, including one hetero atom, which is the N to which they are attached.
  • BA is an antibody.
  • x is an integer from 1 to 4. In some embodiments, x is 4. In some embodiments, x is 2.
  • antibody-steroid conjugates according to according to Formula 1210, 1220, 1230, or 1240: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein R 3 is covalently bonded to L or BA.
  • R 1 and R 2 are, independently, selected from the group consisting of -H, -OH, alkyl, -O-C(O)-alkyl, and halo; or R 1 and R 2 together form
  • R 3 is selected from the group consisting of -alkylene-NR a R b , -X-arylene-Y-NR a R b , -X-heteroarylene-Y-NR a R b , and N-containing heterocycloalkyl; wherein X is absent, -N-, -CH 2 -, or -O-; wherein Y is absent or -CH 2 -; and R 4 is selected from the group consisting of alkyl, aryl, alkylaryl, arylalkyl, heteroaryl, -alkylene-NR a R b , -X-arylene-Y-NR a R b ,
  • R 3 is -NR a R b ; and R 4 is alkyl.
  • BA or L is bonded to an amino group in R 3 , for instance, substituting for a hydrogen atom.
  • R a and R b are, independently in each instance, selected from the group consisting of -H and alkyl; or R a and R b cyclize to form cycloheteroalkyl with three to six ring atoms, including one hetero atom, which is the N to which they are attached.
  • BA is an antibody.
  • x is an integer from 1 to 4.
  • x is 4.
  • x is 2.
  • antibody-steroid conjugates according to according to Formula 1310, 1320, 1330, or 1340: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein R 4 is covalently bonded to L or BA.
  • R 3 is selected from the group consisting of -OH, -O-C(O)-alkyl, -O-aryl, -NR a R b , -alkylene-NR a R b , -X-arylene-Y-NR a R b , -X-heteroarylene-Y-NR a R b , and N-containing heterocycloalkyl; wherein X is absent, -N-, -CH 2 -, or -O-; wherein Y is absent or -CH 2 -; and R 4 is selected from the group consisting of -alkylene-NR a R b , -X-arylene-Y-NR a R b , -X-heteroarylene-Y-NR a R b , and N-containing heterocycloalkyl; wherein X is absent, -N-, -CH 2 -
  • BA or L is bonded to an amino group in R 4 , for instance, substituting for a hydrogen atom.
  • R a and R b are, independently in each instance, selected from the group consisting of -H and alkyl; or R a and R b cyclize to form cycloheteroalkyl with three to six ring atoms, including one hetero atom, which is the N to which they are attached.
  • BA is an antibody.
  • x is an integer from 1 to 4. In some embodiments, x is 4. In some embodiments, x is 2.
  • antibody-steroid conjugates having the following formulas: or mixture thereof; or mixture thereof; or mixture thereof; or mixture thereof; or mixture thereof; or mixture thereof; or mixture thereof; or mixture thereof; or mixture thereof; or mixture thereof; or mixture thereof; or mixture thereof; or mixture thereof; or mixture thereof; or mixture thereof; or mixture thereof; or mixture thereof; or mixture thereof; or mixture thereof; or mixture thereof; or mixture thereof; wherein Ab is an antibody and x is an integer from 1-30. In some embodiments, x is an integer from 1 to 4. In some embodiments, x is 4. In some embodiments, x is 2.
  • antibody-steroid conjugates having the following formulas: or mixtures thereof.
  • Ab is an antibody and x is an integer from 1-30.
  • x is an integer from 1 to 4.
  • x is 4.
  • x is 2.
  • antibody-steroid conjugates having the following formulas: or mixtures thereof; or mixtures thereof; or mixtures thereof; or mixtures thereof; or mixtures thereof; or mixtures thereof; or mixtures thereof; or mixtures thereof; or mixtures thereof; or mixtures thereof; or mixtures thereof; or mixtures thereof; or mixtures thereof; or mixtures thereof.
  • Ab is an antibody and x is an integer from 1-30.
  • x is an integer from 1 to 4.
  • x is 4.
  • x is 2.
  • binding agent conjugates of budesonide or diflorasone are also provided herein.
  • Suitable binding agents for any of the conjugates provided in the instant disclosure include, but are not limited to, antibodies, lymphokines, hormones, growth factors, viral receptors, interleukins, or any other cell binding or peptide binding molecules or substances.
  • the binding agent is an antibody.
  • antibody means any antigen-binding molecule or molecular complex comprising at least one complementarity determining region (CDR) that specifically binds to or interacts with a particular antigen.
  • CDR complementarity determining region
  • antibody includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g., IgM).
  • Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V H ) and a heavy chain constant region.
  • the heavy chain constant region comprises three domains, C H 1, C H 2 and C H 3.
  • Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L ) and a light chain constant region.
  • the light chain constant region comprises one domain (C L 1).
  • the V H and V L regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • Each V H and V L is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the FRs of the antibody may be identical to the human germline sequences, or may be naturally or artificially modified.
  • An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.
  • antibody also includes antigen-binding fragments of full antibody molecules.
  • antigen-binding portion of an antibody, “antigen-binding fragment” of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex.
  • Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains.
  • DNA is known and/or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized.
  • the DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.
  • Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide.
  • CDR complementarity determining region
  • engineered molecules such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigen-binding fragment," as used herein.
  • SMIPs small modular immunopharmaceuticals
  • an antigen-binding fragment of an antibody will typically comprise at least one variable domain.
  • the variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences.
  • the V H and V L domains may be situated relative to one another in any suitable arrangement.
  • the variable region may be dimeric and contain V H -V H , V H -V L or V L -V L dimers.
  • the antigen-binding fragment of an antibody may contain a monomeric V H or V L domain.
  • an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain.
  • variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present disclosure include: (i) V H -C H 1; (ii) V H -C H 2; (iii) V H -C H 3; (iv) V H -C H 1-C H 2; (v) V H -C H 1-C H 2-C H 3; (vi) V H -C H 2-C H 3; (vii) V H -C L ; (viii) V L -C H 1; (ix) V L -C H 2; (x) V L -C H 3; (xi) V L -C H 1-C H 2; (xii) V L -C H 1-C H 2-C H 3; (xiii) V L -C H 2-C H 3; and (xiv) V L
  • variable and constant domains may be e ither directly linked to one another or may be linked by a full or partial hinge or linker region.
  • a hinge region may consist of at least 2 ( e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule.
  • an antigen-binding fragment of an antibody of the present disclosure may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and/or with one or more monomeric V H or V L domain (e.g., by disulfide bond(s)).
  • antigen-binding fragments may be monospecific or multispecific (e.g., bispecific).
  • a multispecific antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen.
  • Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, may be adapted for use in the context of an antigen-binding fragment of an antibody of the present disclosure using routine techniques available in the art.
  • the antibodies of the present disclosure may function through complement-dependent cytotoxicity (CDC) or antibody-dependent cell-mediated cytotoxicity (ADCC).
  • CDC complement-dependent cytotoxicity
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • FcRs Fc receptors
  • NK Natural Killer
  • the constant region of an antibody is important in the ability of an antibody to fix complement and mediate cell-dependent cytotoxicity.
  • the isotype of an antibody may be selected on the basis of whether it is desirable for the antibody to mediate cytotoxicity.
  • the antibodies useful for the compounds herein include human antibodies.
  • the term "human antibody”, as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences.
  • the human antibodies can include amino acid residues not encoded by human germline immunoglobulin sequences ( e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo ) , for example in the CDRs and in particular CDR3.
  • the term “human antibody”, as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • the term "human antibody” does not include naturally occurring molecules that normally exist without modification or human intervention/manipulation, in a naturally occurring, unmodified living organism.
  • the antibodies can, in some embodiments, be recombinant human antibodies.
  • the term "recombinant human antibody”, as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal ( e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res.
  • Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the V H and V L regions of the recombinant antibodies are sequences that, while derived from and related to human germline V H and V L sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • an immunoglobulin molecule comprises a stable four chain construct of approximately 150-160 kDa in which the dimers are held together by an interchain heavy chain disulfide bond.
  • the dimers are not linked via inter-chain disulfide bonds and a molecule of about 75-80 kDa is formed composed of a covalently coupled light and heavy chain (half-antibody).
  • the frequency of appearance of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody.
  • a single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form ( Angal et al. (1993) Molecular Immunology 30:105 ) to levels typically observed using a human IgG1 hinge.
  • the instant disclosure encompasses antibodies having one or more mutations in the hinge, C H 2 or C H 3 region which may be desirable, for example, in production, to improve the yield of the desired antibody form.
  • the antibodies useful for the compounds herein can be isolated antibodies.
  • An "isolated antibody,” as used herein, means an antibody that has been identified and separated and/or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced, is an “isolated antibody” for purposes of the instant disclosure.
  • An isolated antibody also includes an antibody in situ within a recombinant cell. Isolated antibodies are antibodies that have been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and/or chemicals.
  • the antibodies useful for the compounds disclosed herein may comprise one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences from which the antibodies were derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases.
  • the present disclosure includes antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as "germline mutations").
  • Germline mutations A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments which comprise one or more individual germline mutations or combinations thereof.
  • all of the framework and/or CDR residues within the V H and/or V L domains are mutated back to the residues found in the original germline sequence from which the antibody was derived.
  • only certain residues are mutated back to the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2 or CDR3.
  • one or more of the framework and/or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence (i.e ., a germline sequence that is different from the germline sequence from which the antibody was originally derived).
  • the antibodies of the present disclosure may contain any combination of two or more germline mutations within the framework and/or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a particular germline sequence while certain other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residue of a different germline sequence.
  • antibodies and antigen-binding fragments that contain one or more germline mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc.
  • the antibody is a monoclonal antibody, polyclonal antibody, antibody fragment (Fab, Fab', and F(ab)2, minibody, diabody, tribody, and the like), or bispecific antibody.
  • Antibodies herein can be humanized using methods described in US Patent No. 6,596,541 and US Publication No. 2012/0096572 , each incorporated by reference in their entirety.
  • the binding agent binds to an antigen binding partner that is a polypeptide and may be a transmembrane molecule (e.g., receptor) or a growth factor that might be glycosylated or phosphorylated.
  • an antigen binding partner that is a polypeptide and may be a transmembrane molecule (e.g., receptor) or a growth factor that might be glycosylated or phosphorylated.
  • Suitable targets to which the binding agent binds include any target to which steroid delivery is desirable.
  • the binding agent is an antibody, modified antibody, or antigen binding fragment there of that binds a target selected from: AXL, BAFFR, BCMA, BCR-list components, BDCA2, BDCA4, BTLA, BTNL2 BTNL3, BTNL8, BTNL9, C10orf54, CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR9, CCR10, CD11c, CD137, CD138, CD14, CD168, CD177, CD19, CD20, CD209, CD209L, CD22, CD226, CD248, CD25, CD27, CD274, CD276, CD28, CD30, CD300A, CD33, CD37, CD38, CD4, CD40, CD44, CD45, CD46, CD47, CD48, CD5, CD52, CD55, CD56, CD59, CD62E, CD68, CD69, CD70,
  • the binding agent linkers can be bonded to the binding agent, e.g., antibody or antigen-binding molecule, through an attachment at a particular amino acid within the antibody or antigen-binding molecule.
  • Exemplary amino acid attachments that can be used in the context of this aspect of the disclosure include, e.g., lysine (see, e.g., US 5,208,020 ; US 2010/0129314 ; Hollander et al., Bioconjugate Chem., 2008, 19:358-361 ; WO 2005/089808 ; US 5,714,586 ; US 2013/0101546 ; and US 2012/0585592 ), cysteine ( see, e.g., US 2007/0258987 ; WO 2013/055993 ; WO 2013/055990 ; WO 2013/053873 ; WO 2013/053872 ; WO 2011/130598 ; US 2013/0101546 ; and US 7,750,116 ),
  • Linkers can be conjugated via glutamine via transglutaminase-based chemo-enzymatic conjugation (see, e.g., Dennler et al., Bioconjugate Chem. 2014, 25, 569-578 ). Linkers can also be conjugated to an antigen-binding protein via attachment to carbohydrates ( see, e.g., US 2008/0305497 , WO 2014/065661 , and Ryan et al., Food & Agriculture Immunol., 2001, 13:127-130 ) and disulfide linkers ( see, e.g., WO 2013/085925 , WO 2010/010324 , WO 2011/018611 , WO 2014/197854 , and Shaunak et al., Nat.
  • the binding agent is an antibody, and the antibody is bonded to the linker through a lysine residue. In some embodiments, the antibody is bonded to the linker through a cysteine residue.
  • the conjugates described herein can be synthesized by coupling the linker-payloads described herein with a binding agent, e.g., antibody under standard conjugation conditions (see, e.g., Drug Deliv. 2016 Jun;23(5):1662-6 ; AAPS Journal, Vol. 17, No. 2, March 2015 ; and Int. J. Mol. Sci. 2016, 17, 561 , the entireties of which are incorporated herein by reference).
  • Linker-payloads are synthetic intermediates comprising the payload of interest and linking moiety that ultimately serves as the moiety (or portion thereof) that connects the binding agent with the payload.
  • Linker-payloads comprise a reactive group that reacts with the binding agent to form the conjugates described herein.
  • the antibody can be coupled to a linker-payload via one or more cysteine, lysine, or other residue of the antibody.
  • Linker payloads can be coupled to cysteine residues, for example, by subjecting the antibody to a reducing agent, e.g., dithiotheritol, to cleave the disulfide bonds of the antibody, purifying the reduced antibody, e.g., by gel filtration, and subsequently reacting the antibody with a linker-payload containing a reactive moiety, e.g., a maleimido group.
  • Suitable solvents include, but are not limited to water, DMA, DMF, and DMSO.
  • Linker-payloads containing a reactive group can be coupled to lysine residues.
  • Suitable solvents include, but are not limited to water, DMA, DMF, and DMSO.
  • Conjugates can be purified using known protein techniques, including, for example, size exclusion chromatography, dialysis, and ultrafiltration/diafiltration.
  • Binding agents e.g., antibodies
  • the linker-payload comprises a reactive group, e.g., alkyne that is capable of undergoing a 1,3 cycloaddition reaction with an azide.
  • suitable reactive groups include, but are not limited to, strained alkynes, e.g., those suitable for strain-promoted alkyne-azide cycloadditions (SPAAC), cycloalkynes, e.g., cyclooctynes, benzannulated alkynes, and alkynes capable of undergoing 1,3 cycloaddition reactions with azides in the absence of copper catalysts.
  • Suitable alkynes also include, but are not limited to, DIBAC, DIBO, BARAC, DIFO, substituted, e.g., fluorinated alkynes, aza-cycloalkynes, BCN, and derivatives thereof.
  • Linker-payloads comprising such reactive groups are useful for conjugating antibodies that have been functionalized with azido groups.
  • Such functionalized antibodies include antibodies functionalized with azido-polyethylene glycol groups.
  • such functionalized antibody is derived by reacting an antibody comprising at least one glutamine residue, e.g., heavy chain Q295, with a compound according to the formula H 2 N-LL-N 3 , wherein LL is a divalent polyethylene glycol group, in the presence of the enzyme transglutaminase.
  • the antibody Ab is a modified antibody with one or more covalently linked -LL-N 3 groups, or residues thereof.
  • each -LL-N 3 is covalently bonded to an amino acid side chain of a glutamine residue of the antibody.
  • the -LL-N 3 is or can be reacted with a reactive group RG to form a covalent bond to a linker-payload.
  • the -LL-N 3 groups are expressly drawn.
  • the linker-payload includes a cyclodextrin moiety.
  • the linker payload is a compound of Formula (II):
  • Compounds of Formula (II) are linker-payloads that are useful as synthetic intermediates in the synthesis of the conjugates described herein. These linker-payloads comprise a reactive group that can react with an antibody to form the conjugates described herein.
  • R 1 and R 2 are, each, independently, -H, alkyl, or -OH. In some examples of Formula (II), one of R 1 or R 2 is -H, alkyl, or -OH. In some examples of Formula (II), both R 1 and R 2 are either -H, alkyl, or -OH.
  • R 1 and R 2 together form
  • R 4 is -RL.
  • R 4 is RL-NR a -aryl.
  • R 4 is alkyl.
  • R 4 is arylalkyl,
  • R 4 is aryl.
  • R 4 is N-containing heterocycloalkyl.
  • the alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl is optionally substituted.
  • R 5 is halo. In some examples of Formula (II), R 5 is fluoro. In some examples of Formula (II), one of R 5 is halo. In some examples of Formula (II), R 5 is halo and n is 2. In some examples of Formula (II), R 5 is -F and n is 1. In some examples of Formula (II), R 5 is -F and n is 2.
  • R 3 is RL. In some examples of Formula ( II ), R 3 is RL-NR a -aryloxy-. In some other examples of Formula (II), R 3 is -OH. In some other examples of Formula (II), R 3 is alkyl-C(O)-O-. In some other examples of Formula (II), R 3 is heteroalkyl. In some other examples of Formula (II), R 3 is -N-R a R b . In some other examples of Formula (II), R 3 is aryl. In some other examples of Formula ( II ), R 3 is aryloxy. In some other examples of Formula (II), alkyl-C(O)-O-, heteroalkyl, or aryloxy is optionally substituted with -NR a R b or halo.
  • R 3 is -OH. In some examples of Formula ( II ), R 3 is alkyl-C(O)-O-. In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is heteroalkyl. In some examples of Formula ( II ), R 3 is or In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is -NR a R b . In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is aryloxy.
  • R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is In some examples of Formula (II), R 3 is in some examples of Formula (II), R 3 is in some examples of Formula (II), R 3
  • n is an integer from 0-19. In some examples, n is 0. In some other examples, n is 1. In certain examples, n is 2. In some other examples, n is 3. In certain examples, n is 4. In some examples, n is 5. In some other examples, n is 6. In certain examples, n is 7. In some other examples, n is 8. In certain examples, n is 9. In some examples, n is 10. In some other examples, n is 11. In certain examples, n is 12. In some other examples, n is 13. In certain examples, n is 14. In some examples, n is 15. In some other examples, n is 16. In certain examples, n is 17. In some other examples, n is 18. In certain examples, n is 19.
  • the compound of Formula (IIa2) has the following structure: wherein:
  • R 5 is halo. In some examples of Formula ( IIb ), R 5 is fluoro. In some examples of Formula (IIb), n is at least 2, and two of R 5 is halo. In some examples of Formula (IIb), R 5 is F and n is 1. In some examples of Formula (IIb), R 5 is -F.
  • R 4 is alkyl. In some examples of Formula (IIb), R 4 is methyl, ethyl, n -propyl, i -propyl, n -butyl, s -butyl, t -butyl, i -butyl, a pentyl moiety, a hexyl moiety, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some examples of Formula (IIb), R 4 is n -propyl.
  • the compound of Formula (IIb) has the following structure: wherein:
  • R 5 is -halo. In some examples of Formula (IIc), R 5 is fluoro. In some examples of Formula (IIc), one of R 5 is halo. In some examples of Formula (IIc), two of R 5 is halo. In some examples of Formula (IIc), R 5 is -F and n is 2.
  • R 1 is C H 3.
  • R 1 is OH.
  • R 1 is H.
  • R 2 is C H 3.
  • R 2 is OH.
  • R 2 is H.
  • R 1 is CH 3 and R 2 is C H 3.
  • R 1 is CH 3 and R 2 is OH.
  • R 1 is CH 3 and R 2 is H.
  • R 1 is OH and R 2 is C H 3.
  • R 1 is OH and R 2 is OH.
  • R 1 is H and R 2 is H.
  • R 1 is H and R 2 is OH.
  • R 1 is H and R 2 is H.
  • the compound of Formula (IIc) has the following structure: wherein:
  • R 3 is ;
  • R 1 and R 2 are each, independently, -H, alkyl, alkyl-C(O)-O-, -OH, or halo; or R 1 and R 2 together form wherein R 4 is alkyl, aryl, arylalkyl, or an N-containing heterocycloalkyl; wherein the alkyl, aryl, arylalkyl, and N-containing heterocycloalkyl are optionally substituted with -NR a R b ;
  • the phrase "reactive linker,” or the abbreviation "RL” refers to a monovalent group that comprises a reactive group and linking group, depicted as wherein RG is the reactive group and L is the linking group.
  • the linking group is any divalent moiety that bridges the reactive group to a payload.
  • the linking group also includes any trivalent moiety that bridges the reactive group, a cyclodextrin moiety, and a payload.
  • the reactive linkers (RL), together with the payloads to which they are bonded, comprise intermediates ("linker-payloads") useful as synthetic precursors for the preparation of the antibody steroid conjugates described herein.
  • the reactive linker contains a reactive group ("RG”), which is a functional group or moiety that reacts with a reactive portion of an antibody, modified antibody, or antigen binding fragment thereof.
  • RG reactive group
  • the "reactive group” is a functional group or moiety (e.g ., maleimide or NHS ester) that reacts with a cysteine or lysine residue of an antibody or antigen-binding fragment thereof.
  • the "reactive group” is a functional group or moiety that is capable of undergoing a click chemistry reaction.
  • the reactive group is an alkyne that is capable of undergoing a 1,3 cycloaddition reaction with an azide.
  • suitable reactive groups include, but are not limited to, strained alkynes, e.g., those suitable for strain-promoted alkyne-azide cycloadditions (SPAAC), cycloalkynes, e.g., cyclooctynes, benzannulated alkynes, and alkynes capable of undergoing 1,3 cycloaddition reactions with alkynes in the absence of copper catalysts.
  • Suitable alkynes also include, but are not limited to, DIBAC, DIBO, BARAC, substituted, e.g., fluorinated alkynes, aza-cycloalkynes, BCN, and derivatives thereof.
  • Linker-payloads comprising such reactive groups are useful for conjugating antibodies that have been functionalized with azido groups.
  • Such functionalized antibodies include antibodies functionalized with azido-polyethylene glycol groups.
  • such functionalized antibody is derived by reacting an antibody comprising at least one glutamine residue, e.g., heavy chain Q295, with a compound according to the formula H 2 N-LL-N 3 , wherein LL is, for example, a divalent polyethylene glycol group, or wherein LL is a trivalent group which includes polyethylene glycol and a cyclodextrin moiety, in the presence of the enzyme transglutaminase.
  • the antibody is a functionalized antibody having the following structure: wherein Ab is an antibody, R is hydrocarbyl, n is an integer from 1 to 10, w is an integer from 1-10. In certain embodiments, R is ethylene. In certain embodiments, n is 3.
  • w is 2 or 4.
  • the reactive group is an alkyne, e.g., which can react via click chemistry with an azide, e.g., to form a click chemistry product, e.g., its regioisomer, or a mixture thereof.
  • the reactive group is an alkyne, e.g., which can react via click chemistry with an azide, e.g., to form a click chemistry product, e.g., In some examples, the reactive group is an alkyne, e.g., which can react via click chemistry with an azide, e.g., to form a click chemistry product, e.g., its regioisomer, or a mixture thereof.
  • the reactive group is a functional group, e.g., ,which reacts with a cysteine residue on an antibody or antigen-binding fragment thereof, to form a bond thereto, e.g., wherein Ab refers to an antibody or antigen-binding fragment thereof and S refers to the S atom on a cysteine residue through which the functional group bonds to the Ab.
  • the reactive group is a functional group, e.g., which reacts with a lysine residue on an antibody or antigen-binding fragment thereof, to form a bond thereto, e.g., wherein Ab refers to an antibody or antigen-binding fragment thereof and -NH- refers to the end of the lysine residue through which the functional group bonds to the Ab.
  • this N atom on a lysine residue through which the functional group bonds is indicated herein as the letter N above a bond, e.g.,
  • RL is a monovalent moiety of Formula (RL A ); RG-(Sp 1 ) q -(A) z -(NR a ) s -(B) t -(CH 2 ) u -(O) v -( SP 2 ) w -(RL A );
  • RL is RG-(SP 1 ) q -(A) z -. In some embodiments, RL is RG-(Sp 1 ) q -(A) 2 -. In some embodiments, RL is a moiety of Formula (RL A1 ) wherein R AA1 and R AA2 are each, independently, amino acid side chains.
  • SP 1 is a divalent polyethylene glycol group and RG is a group comprising an alkyne that is capable of undergoing a 1,3-cycloaddition reaction with an azide.
  • RL has the following structure: RG-(SP 1 ) q -Z 1 -Z 2 -Z 3 0-1 - wherein:
  • BL is a trivalent moiety of Formula (BL B ); RG N -(SP 1 ) q -(A) z -(NR a ) s -(B) t -(CH 2 ) u -(O) v -( SP 2 ) w -( BL B );
  • the cyclodextrin (CD) is bonded directly to an amino acid residue, such as a lysine amino acid residue. This means that the CD is one bond position away from the lysine amino acid covalent linker.
  • the covalent linker is also bonded directly to a payload moiety. This means that the covalent linker is one bond position away from a payload such as, but not limited to a steroid payload set forth herein.
  • the covalent linker is also bonded directly to a CD moiety. This means that the covalent linker is one bond position away from a CD, such as the CD(s) set forth herein.
  • the covalent linker is a lysine amino acid or a derivative thereof.
  • the CD is bonded indirectly to a covalent linker in a linking group (e.g., a BL).
  • a linking group e.g., a BL
  • the CD is more than one bond position away from the covalent linker.
  • the CD is bonded through another moiety to the covalent linker.
  • the CD may be bonded to a maleimide group which is bonded to a polyethylene glycol group which is bonded to the covalent linker.
  • the covalent linker is also bonded indirectly to a payload moiety. This means that the covalent linker is more than one bond position away from a payload such as, but not limited to a steroid payload set forth herein.
  • the covalent linker is bonded through another moiety to the payload.
  • the covalent linker may be bonded to a dipeptide, such as but not limited to Val-Ala or Val-Cit, which may be bonded to para-amino benzoyl which may be bonded to the payload.
  • the covalent linker is also bonded indirectly to a cyclodextrin moiety. This means that the covalent linker is more than one bond position away from a cyclodextrin, such as the cyclodextrins set forth herein. This also means that the covalent linker is bonded through another moiety to the cyclodextrin.
  • the covalent linker may be bonded to a polyethylene glycol group which may be bonded to reactive group which may be bonded to the cyclodextrin.
  • the covalent linker is a lysine amino acid or a derivative thereof.
  • BL is -RG N -(SP 1 ) q -(A) z -. In some embodiments, BL is -RG N -(SP 1 ) q -(A) 2 -. In some embodiments, BL is a moiety of Formula (BL B1 ) wherein R AA1 and R AA2 are each, independently, amino acid side chains. R AA3 is an amino acid side chain that is bonded directly or indirectly to a cyclodextrin moiety.
  • Formula RL B1 SP 1 is a divalent polyethylene glycol group and RG N is a 1,3-cycloaddition reaction adduct of the reaction between an alkyne and an azide.
  • A is in some of these examples, R AA1 is an amino acid side chain, R AA2 is an amino acid side chain, and R AA3 is an amino acid side chain that is bonded directly or indirectly to a cyclodextrin moiety.
  • A is wherein represents a direct or indirect bond to a cyclodextrin moiety.
  • CD is, independently in each instance, selected from In some examples, the CD is In some examples, the CD is In some examples, the CD is In some examples, the CD is In some examples, the CD is In some examples, the CD is In some examples, the CD is in some examples, the CD is, the CD is
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • the RL attaches to a tertiary amine.
  • the RL may bond to the tertiary amine as follows:
  • RG is selected from a click-chemistry reactive group.
  • RG is selected from a group which reacts with a cysteine or lysine residue on an antibody or an antigen-binding fragment thereof.
  • RG is In some examples, RG is In other examples, RG is In some other examples, RG is In some other examples, RG is In some examples, RG is In other examples, RG is In other examples, RG is In other examples, RG is RG is In other examples, RG is
  • SP 1 may be selected from: In some examples, SP 1 is In some other examples, SP 1 is In other examples, SP 1 is In still other examples, SP 1 is In some other examples, SP 1 is
  • subscripts a, b, and c are independently, in each instance, an integer from 1 to 20.
  • SP 1 may be selected from: or
  • SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is . In some examples, SP 1 is . In some examples, SP 1 is . In some examples, SP 1 is
  • SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is In some examples, SP 1 is
  • RL-SP 1 may be selected from the group consisting of: In some of these examples, subscripts b, c, and d are independently, in each instance, an integer from 1 to 20.
  • RL-SP 1 - is In some examples RL-SP 1 is In some examples RL-SP 1 is In some examples RL-SP 1 is In some examples RL-Sp 1 is In some examples RL-SP 1 is In some examples RL-SP 1 is
  • RL-SP 1 is selected from:
  • A is a peptide selected from valine-citrulline, citrulline-valine, lysine-phenylalanine, phenylalanine-lysine, valine-asparagine, asparagine-valine, threonine-asparagine, asparagine-threonine, serine-asparagine, asparagine-serine, phenylalanine-asparagine, asparagine-phenylalanine, leucine-asparagine, asparagine-leucine, isoleucine-asparagine, asparagine-isoleucine, glycine-asparagine, asparagine-glycine, glutamic acid-asparagine, asparagine-glutamic acid, citrulline-asparagine, asparagine-citrulline, alanine-asparagine, or asparagine-alanine.
  • A is valine-citrulline or citrulline-valine.
  • A is valine-alanine or alanine-valine.
  • A is valine.
  • A is alanine
  • A is citrulline
  • A is In some of these examples, R AA1 is an amino acid side chain, and wherein R AA2 is an amino acid side chain.
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R a is H
  • R a is alkyl
  • R a is methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, or pentyl.
  • B is aryl
  • B is phenyl
  • B is phenyl or pyridinyl.
  • B is:
  • R 10 is alkyl, alkenyl, alkynyl, alkoxy, aryl, alkylaryl, arylalkyl, halo, haloalkyl, haloalkoxy, heteroaryl, heterocycloalkyl, hydroxyl, cyano, nitro, NR a R b , or azido.
  • subscripts p and m are independently, in each instance, selected from an integer from 0 to 4.
  • B is:
  • p is 0, 1, 2, 3 or 4.
  • R 1 is, independently at each occurrence, alkyl, alkoxy, haloalkyl, or halo.
  • R 1 is alkyl.
  • R 1 is alkoxy.
  • R 1 is haloalkyl.
  • R 1 is halo.
  • the -(NR a ) s -(B) t (CH 2 ) u -(O) v -( SP 2 ) w is:
  • linker-payloads of budesonide or diflorasone are also linker-payloads of budesonide or diflorasone.
  • a linker-payload having the following structure: wherein RL is a reactive linker.
  • linker-payloads include, but are not limited to: and and salts thereof.
  • the present disclosure includes methods of treating diseases, conditions, or disorders e.g. , inflammatory diseases and autoimmune disorders, or managing symptoms thereof, comprising administering a therapeutically effective amount of one or more of the compounds disclosed herein. Included are any diseases, disorders, or conditions associated with the glucocorticoid receptor, glucocorticoid binding, and/or glucocorticoid receptor signaling. Such methods comprise administering a steroid payload or protein conjugate thereof described herein to a patient.
  • glucocorticoid receptor comprising administering a compound of Formula ( I ), ( I ) 1 , or protein conjugate thereof, e.g., compound of Formula ( III ) to a patient having said disease, disorder, or condition.
  • a protein conjugate of a compound of Formula selected from the group consisting of ( A ), ( A 1 ), ( A 2 ), ( A 3 ), ( A 4 ), ( A 5 ), ( A 6 ), ( A 7 ), ( I ), ( I 1 ), ( PIa ), ( PIb-1 ), ( PIb-2 ), PIc-1 ), ( PIc-2 ), ( PId-1 ), ( PId-2 ), ( PIe-1 ), ( PIe-2 ), ( PII ), ( PIIa ), ( PIIb ), ( PIII ), ( PIIIa ), ( PIIIb ), ( PIV ), ( PV ), ( PVa ), ( PVb ), ( PVI ), ( PVII ), ( PVIIa ), ( PVIIb ), ( PVIIb-1 ), ( PVIIb-2 ), ( PVIIb-2 ), ( PVIIb-2
  • the disease, disorder, or condition is allergic state, including but not limited to asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, and serum sickness; dermatologic diseases, including but not limited to bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, and severe erythema multiforme (Stevens-Johnson syndrome); endocrine disorders, including but not limited to primary or secondary adrenocortical insufficiency, congenital adrenal hyperplasia, hypercalcemia associated with cancer, and nonsuppurative thyroiditis; gastrointestinal diseases; hematologic disorders, including but not limited to acquired (autoimmune) hemolytic anemia, congenital (erythroid) hypoplastic anemia (Diamond-Blackfan anemia), idiopathic thrombocytopenic purpura in adults, pure red cell aplasia, and secondary thrombocytopenia; trichinos
  • set forth herein is a method for treating a disease, disorder, or condition selected from an autoimmune disease, an allergy, arthritis, asthma, a breathing disorder, a blood disorder, a cancer, a collagen disease, a connective tissue disorders, a dermatological disease, an eye disease, an endocrine problem, an immunological disease, an inflammatory disease, an intestinal disorders, a gastrointestinal disease, a neurological disorder, an organ transplant condition, a rheumatoid disorder, a skin disorder, a swelling condition, a wound healing condition, and a combination thereof comprising administering a steroid payload or conjugate thereof described herein.
  • a disease, disorder, or condition selected from an autoimmune disease, an allergy, arthritis, asthma, a breathing disorder, a blood disorder, a cancer, a collagen disease, a connective tissue disorders, a dermatological disease, an eye disease, an endocrine problem, an immunological disease, an inflammatory disease, an intestinal disorders, a gastrointestinal disease, a neurological disorder, an organ transplant condition,
  • the autoimmune disorder is selected from multiple sclerosis, autoimmune hepatitis, shingles, systemic lupus erythematosus (i.e., lupus), myasthenia gravis, Duchenne muscular dystrophy, and sarcoidosis.
  • the breathing disorder is selected from asthma, chronic obstructive pulmonary disease, bronchial inflammation, and acute bronchitis.
  • the cancer is selected from leukemia, lymphoblastic leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, Hodgkin's lymphoma, Non-Hodgkin's lymphoma (NHL), and multiple myeloma.
  • the collagen disease is systemic lupus erythematosus.
  • the eye disease is keratitis.
  • the endocrine problem is selected from Addison's Disease, adrenal insufficiency, adrenocortical, and congenital adrenal hyperplasia.
  • the inflammatory disease is selected from joint inflammation, tendon inflammation, bursitis, epicondylitis, Crohn's disease, inflammatory bowels disease, lipid pneumonitis thyroiditis, urticaria (hives), pericarditis, nephrotic syndrome, and uveitis.
  • the intestinal disorder is selected from ulcerative colitis, Crohn's disease, and inflammatory bowels disease.
  • the rheumatoid disorder is selected from rheumatoid arthritis, polymyalgia rheumatic, psoriatic arthritis, ankylosing spondylitis, and systemic lupus erythematosus.
  • the skin disorder is selected from psoriasis, eczema, and poison ivy.
  • the neurological disorder is chronic inflammatory demyelinating polyradiculoneuropathy.
  • the compounds described herein are administered to a patient to treat an acute inflammatory event, including but not limited to shock, brain edema, and graft-vs-host disease.
  • an acute inflammatory event including but not limited to shock, brain edema, and graft-vs-host disease.
  • the compounds described herein are administered to treat lympholytic effects, including but not limited to those associated with hematological malignancies, e.g., leukemias, lymphomas, and myelomas.
  • set forth herein is a method for reducing inflammation in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a steroid or conjugate thereof described herein.
  • set forth herein is a method for modulating the immune system in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a steroid or conjugate thereof described herein.
  • set forth herein is a method for modulating cortisol levels in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a steroid or conjugate thereof described herein.
  • set forth herein is a method of reducing lymphocyte migration in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a steroid or conjugate thereof described herein.
  • set forth herein is a method of treating hypercalcemia due to cancer, Meniere's disease, a migraine headache, a cluster headache, a severe aphthous ulcer, laryngitis, severe tuberculosis, a Herxheimer reaction to syphilis, a decompensated heart failure, allergic rhinitis or nasal polyps, comprising administering to a subject in need thereof a steroid payload or conjugate thereof described herein.
  • the compounds disclosed herein can be used for treating inflammatory bowel disease, Crohn's disease, or ulcerative colitis.
  • the disease, disorder, or condition is a chronic inflammatory condition, including but not limited to asthma, skin infections, and ocular infections.
  • compounds described herein are used for immunosuppression in patients undergoing organ transplantation.
  • the steroid payloads and conjugates thereof described herein are administered to a patient to treat a nervous disorder associated with GR signaling, including but not limited to psychiatric disorders such as schizophrenia, drug addiction, post-traumatic stress disorder (PTSD), and mood disorders, substance abuse, stress, and anxiety.
  • a nervous disorder associated with GR signaling including but not limited to psychiatric disorders such as schizophrenia, drug addiction, post-traumatic stress disorder (PTSD), and mood disorders, substance abuse, stress, and anxiety.
  • the steroid payloads and conjugates thereof described herein are administered to a patient to treat a visual system disorder, including but not limited to ocular inflammation (e.g., conjunctivitis, keratitis, uveitis), macular edema, and macular degeneration.
  • the steroid payloads and conjugates thereof described herein are administered to a patient to treat a cardiovascular disorder.
  • the steroid payloads and conjugates thereof described herein are administered to a patient to treat a glucose and/or liver metabolism disorder. In some embodiments, the steroid payloads and conjugates thereof described herein are administered to a patient to treat a musculoskeletal system disorder. In some embodiments, the steroid payloads and conjugates thereof described herein are administered to a patient to treat a cutaneous inflammatory condition, such as eczema and psoriasis.
  • the protein conjugates described herein provide a means for targeted delivery of its steroid payload to particular cells or organ systems, thereby reducing or preventing side effects that result from administration of the free unconjugated steroid payload.
  • methods for treating a disease, disorder, or condition associated with the glucocorticoid receptor comprising administering a conjugate of Formula (I) or (I) 1 , to a patient having said disease, disorder, or condition, wherein the side effects associated with administration of the free steroid payload of said conjugate is reduced.
  • a compound of Formula (I) or (I) 1 to a cell comprising contacting said cell with a protein conjugate the compound of Formula (I) or (I) 1 , wherein the protein conjugate comprises an antibody or antigen binding fragment thereof that binds a surface antigen of said cell.
  • the compounds described herein can be administered alone or together with one or more additional therapeutic agents.
  • the one or more additional therapeutic agents can be administered just prior to, concurrent with, or shortly after the administration of the compounds described herein.
  • the present disclosure also includes pharmaceutical compositions comprising any of the compounds described herein in combination with one or more additional therapeutic agents, and methods of treatment comprising administering such combinations to subjects in need thereof.
  • Suitable additional therapeutic agents include, but are not limited to: a second glucocorticoid, an autoimmune therapeutic agent, a hormone, a biologic, or a monoclonal antibody. Suitable therapeutic agents also include, but are not limited to any pharmaceutically acceptable salts, acids or derivatives of a compound set forth herein.
  • the compounds described herein can also be administered and/or co-formulated in combination with antivirals, antibiotics, analgesics, corticosteroids, steroids, oxygen, antioxidants, COX inhibitors, cardioprotectants, metal chelators, IFN-gamma, and/or NSAIDs.
  • multiple doses of a compound described herein may be administered to a subject over a defined time course.
  • the methods according to this aspect of the disclosure comprise sequentially administering to a subject multiple doses of a compound described herein.
  • sequentially administering means that each dose of the compound is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months).
  • the present disclosure includes methods which comprise sequentially administering to the patient a single initial dose of a compound described herein, followed by one or more secondary doses of the compound, and optionally followed by one or more tertiary doses of the compound.
  • the “initial dose” is the dose which is administered at the beginning of the treatment regimen (also referred to as the “baseline dose”);
  • the “secondary doses” are the doses which are administered after the initial dose;
  • the “tertiary doses” are the doses which are administered after the secondary doses.
  • the initial, secondary, and tertiary doses can all contain the same amount the compound described herein, but generally can differ from one another in terms of frequency of administration.
  • the amount of the compound contained in the initial, secondary and/or tertiary doses varies from one another (e.g ., adjusted up or down as appropriate) during the course of treatment.
  • two or more (e.g., 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as "loading doses" followed by subsequent doses that are administered on a less frequent basis (e.g. , "maintenance doses").
  • each secondary and/or tertiary dose is administered 1 to 26 ( e.g. , 1, 11 ⁇ 2, 2, 21 ⁇ 2, 3, 31 ⁇ 2, 4, 41 ⁇ 2, 5, 51 ⁇ 2, 6, 61 ⁇ 2, 7, 71 ⁇ 2, 8, 81 ⁇ 2, 9, 91 ⁇ 2, 10, 101 ⁇ 2, 11, 111 ⁇ 2, 12, 121 ⁇ 2, 13, 131 ⁇ 2, 14, 141 ⁇ 2, 15, 151 ⁇ 2, 16, 161 ⁇ 2, 17, 171 ⁇ 2, 18, 181 ⁇ 2, 19, 191 ⁇ 2, 20, 201 ⁇ 2, 21, 211 ⁇ 2, 22, 221 ⁇ 2, 23, 231 ⁇ 2, 24, 241 ⁇ 2, 25, 251 ⁇ 2, 26, 261 ⁇ 2, or more) weeks after the immediately preceding dose.
  • the phrase "the immediately preceding dose,” as used herein, means, in a sequence of multiple administrations, the dose the compound which is administered to a patient prior to the administration of the very next dose in the sequence with no intervening doses.
  • the methods according to this aspect of the disclosure may comprise administering to a patient any number of secondary and/or tertiary doses of the compound.
  • any number of secondary and/or tertiary doses of the compound may comprise administering to a patient any number of secondary and/or tertiary doses of the compound.
  • only a single secondary dose is administered to the patient.
  • two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient.
  • only a single tertiary dose is administered to the patient.
  • two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.
  • the administration regimen may be carried out indefinitely over the lifetime of a particular subject, or until such treatment is no longer therapeutically needed or advantageous.
  • each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks or 1 to 2 months after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 12 weeks after the immediately preceding dose.
  • the frequency at which the secondary and/or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the needs of the individual patient following clinical examination.
  • the present disclosure includes administration regimens in which 2 to 6 loading doses are administered to a patient at a first frequency (e.g. , once a week, once every two weeks, once every three weeks, once a month, once every two months, etc.), followed by administration of two or more maintenance doses to the patient on a less frequent basis.
  • a first frequency e.g. , once a week, once every two weeks, once every three weeks, once a month, once every two months, etc.
  • the maintenance doses may be administered to the patient once every six weeks, once every two months, once every three months, etc.
  • compositions of the compounds and/or conjugates described herein e.g., the compounds of Formula (I) and (II), e.g., compositions comprising a compound described herein, a salt, stereoisomer, polymorph thereof, and a pharmaceutically acceptable carrier, diluent, and/or excipient.
  • suitable carriers, diluents and excipients include, but are not limited to: buffers for maintenance of proper composition pH (e.g., citrate buffers, succinate buffers, acetate buffers, phosphate buffers, lactate buffers, oxalate buffers and the like), carrier proteins (e.g.
  • saline e.g. , human serum albumin
  • polyols e.g. , trehalose, sucrose, xylitol, sorbitol, and the like
  • surfactants e.g. , polysorbate 20, polysorbate 80, polyoxolate, and the like
  • antimicrobials and antioxidants.
  • set forth herein is a method of treating a disease, disorder or condition including administering to a patient having said disorder a therapeutically effective amount of a compound of Formula I, III, or a pharmaceutical composition thereof.
  • set forth herein is a method of treating a disease, disorder or condition including administering to a patient having said disorder a therapeutically effective amount of a compound set forth herein, or a pharmaceutical composition thereof.
  • set forth herein is a method of treating a disease, disorder or condition selected from the group consisting of an immunological disease, autoimmune disease, inflammation, asthma, or an inflammatory bowel disorder, Crohn's disease, ulcerative colitis.
  • set forth herein is a method of treating a disease, disorder or condition by targeting an antigen, e.g. , cell-surface expressing antigen, to which steroid delivery can achieve a therapeutic benefit comprising administering the conjugates described herein.
  • an antigen e.g. , cell-surface expressing antigen
  • the antigen is AXL, BAFFR, BCMA, BCR-list components, BDCA2, BDCA4, BTLA, BTNL2 BTNL3, BTNL8,BTNL9, C10orf54, CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR9, CCR10, CD11c, CD137, CD138, CD14, CD168, CD177, CD19, CD20, CD209, CD209L, CD22, CD226, CD248, CD25, CD27, CD274, CD276, CD28, CD30, CD300A, CD33, CD37, CD38, CD4, CD40, CD44, CD45, CD47, CD46, CD48, CD5, CD52, CD55, CD56, CD59, CD62E, CD68, CD69, CD70, CD74, CD79a, CD79b, CD8, CD80, CD86, CD90.2, CD96, CLEC12A, CLEC12B, CLEC7A, CLEC9A, C10orf54
  • set forth herein is a method for treating a disease, disorder, or condition selected from an immunological disease, an autoimmune disease, an inflammatory disease, a dermatological disease, or a gastrointestinal disease.
  • the disease is Crohn's disease, ulcerative colitis, Cushing's syndrome, adrenal insufficiency, or congenital adrenal hyperplasia.
  • the disease is inflammation, asthma, or an inflammatory bowel disorder.
  • the disease is an autoimmune diseases selected from multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, psoriasis, or eczema.
  • set forth herein is a method for reducing or ameliorating the side effects of chemotherapy, wherein the method includes administering to a patient having said disorder a therapeutically effective amount of a compound or a composition described herein.
  • set forth herein is a method for reducing or ameliorating the side effects of immunosuppressive therapy, wherein the method includes administering to a patient having said disorder a therapeutically effective amount of a compound or a composition described herein.
  • set forth herein is a method for treating cancer, wherein the method includes administering to a patient having said disorder a therapeutically effective amount of a compound or a composition described herein.
  • the cancer is selected from acute lymphoblastic leukemia, chronic lymphoblastic leukemia, Hodgkin's lymphoma, Non-Hodgkin's lymphoma (NHL), or multiple myeloma, as well as others.
  • Reagents and solvents were obtained from commercial sources such as Sinopharm Chemical Reagent Co. (SCRC), Sigma-Aldrich, Alfa, or other vendors, unless explicitly stated otherwise.
  • SCRC Sinopharm Chemical Reagent Co.
  • Sigma-Aldrich Sigma-Aldrich
  • Alfa Alfa
  • Method A for HPLC-MS measurement included, as the Mobile Phase: A: Water (0.01% trifluoroacetic acid TFA) and B: acetonitrile (0.01 % TFA).
  • the Gradient Phase was 5% of B that was increased to 95% of B over a time period of 15 minutes (min) and at a flow rate of 1.0 mL/min.
  • the column used was a SunFire C18, 4.6x50 mm, 3.5 ⁇ m.
  • the column temperature was 50 °C.
  • the detectors included an Analog to Digital Converter ELSD (Evaporative Light-scattering Detector, hereinafter "ADC ELSD”), DAD (Diode array detector, 214 nm and 254 nm), and Electrospray Ionization-Atmospheric Pressure Ionization (ES-API).
  • ADC ELSD Electronic Light-scattering Detector
  • DAD Diode array detector, 214 nm and 254 nm
  • ES-API Electrospray Ionization-Atmospheric Pressure Ionization
  • Method B for HPLC-MS measurements included, as the Mobile Phase: A: Water (10mM NH 4 HCO 3 ) and B: acetonitrile.
  • the Gradient Phase was 5% of B that was increased to 95% of B over a time period of 15 min and a flow rate of 1.0 mL/min.
  • the column used was a XBridge C18, 4.6x50 mm, 3.5 ⁇ m.
  • the column temperature was 50 °C.
  • the detectors included an ADC ELSD, DAD (214 nm and 254 nm), and a mass-selcetive detector (MSD ES-API).
  • Method A for LC-MS measurement was performed on a WATERS 2767 instrument.
  • the column was a Shimadzu Shim-Pack, PRC-ODS, 20x250mm, 15 ⁇ m, two connected in series.
  • the Mobile Phase was A: Water (0.01% TFA ) and B: acetonitrile (0.01% TFA).
  • the Gradient Phase was 5% of B that was increased to 95% of B over a time period of 3 min and at a flow rate of 1.8 - 2.3 mL/min.
  • the column used was a SunFire C18, 4.6x50 mm, 3.5 ⁇ m.
  • the column temperature was 50 °C.
  • the detectors included an Analog to Digital Converter ELSD (Evaporative-Light Scattering Detector), DAD (Diode Array Detector) (214 nm and 254 nm), and ES-API.
  • ELSD Analog to Digital Converter
  • DAD Dynamiconitrile
  • Method B for LC-MS measurement was performed on a Gilson GX-281 instrument.
  • the column was an Xbridge Prep C18 10 um OBD, 19x250 mm.
  • the Mobile Phase was A: Water (10mM NH 4 HCO 3 ) and B: Acetonitrile.
  • the Gradient Phase was 5% of B that was increased to 95% of B over a time period of 3 min and at a flow rate of1.8 - 2.3 mL/min.
  • the column used was an XBridge C18, 4.6x50 mm, 3.5 ⁇ m.
  • the column temperature was 50 °C.
  • the detectors included ADC ELSD, DAD (214 nm and 254 nm), and Mass Selective Detector (MSD) (ES-API).
  • Preparative high-pressure liquid chromatography was performed on a Gilson GX-281 instrument. Two solvent systems were used, one acidic and one basic.
  • the acidic solvent system included a Waters SunFire 10 ⁇ m C18 column (100 ⁇ , 250 x 19 mm).
  • Solvent A for prep-HPLC was 0.05% TFA in water and solvent B was acetonitrile.
  • the elution condition was a linear gradient that increased solvent B from 5% to 100% over a time period of 20 minutes and at a flow rate of 30 mL/min.
  • the basic solvent system included a Waters Xbridge 10 ⁇ m C18 column (100 ⁇ , 250 x 19 mm).
  • Solvent A for prep-HPLC was 10 mM ammonium bicarbonate (NH 4 HCO 3 ) in water and solvent B was acetonitrile.
  • the elution condition was a linear gradient that increased solvent B from 5% to 100% over a time period of 20 minutes and at a flow rate of 30 mL/min.
  • This example demonstrates one method for making chemical derivatives of Desonide with stereochemical control at the C 22 -position.
  • the C 22 position is identified for compounds 7 , 8 and 11 with an asterisk, i.e., *.
  • the synthesis of steroids with stereochemical control at the C 22 -position was performed following the synthetic route depicted in FIGs. 1 and 2 .
  • Desonide ( 1 ) which is a generic name for (1 S ,2 S ,4 R, 8 S ,9 S ,11 S ,12 S ,13 R )-11-hydroxy-8-(2-hydroxyacetyl)-6,6,9,13-tetramethyl-5,7-dioxapentacyclo[10.8.0.0 2,9 .0 4,8 .0 13,18 ]icosa-14,17-dien-16-one, was reacted with isobutyric anhydride (compound 2 ) to produce intermediate 3 by esterification at the primary alcohol position of compound 1 .
  • Alcohols 5 and ester 6 were separated by column chromatography.
  • Each alcohol 5 or ester 6 was individually, reacted with diethylamine to remove Fmoc-group or with Fe/NH 4 Cl to reduce nitro to provide epimer compounds 7 and 8 having both R/S stereochemistry at C 22 , respectively.
  • R and S epimers were separated and their R -and S- configurations were identified.
  • the R-epimers of, for example, compounds 7 and 8 in FIG. 1 were isolated and confirmed to be the majority stereoisomer by greater 90% by 1 H NMR.
  • the C 22 configuration of each epimer was determined by 2D-NOESY spectroscopic studies.
  • Table 1 presents steroids made using the methods described herein. Table 1 - Structure and Chemical-Physical Properties of Compounds Cpd. No C 22 Structure MF MW (Cal. ) MS (M+H) HPLC purity (%) cLog P 7-1 S C 28 H 33 NO 6 479.6 480.2 96 2.53 7-1 R C 28 H 33 NO 6 479.6 480.3 100 2.53 8-1 R C 32 H 39 NO 7 549.7 550.3 96 4.22 7-2 R / S C 29 H 35 NO 6 493.6 494.3 98 2.59 8-2 R / S C 33 H 41 NO 7 563.7 564.3 98 4.28 8-3 R / S C 27 H 37 NO 6 471.6 472.2 96 1.63 7-4 R C 27 H 37 NO 6 471.6 472.2 96 1.63 11-1 R / S C 25 H 35 NO 5 429.6 429.9 100 2.63 11-2 R / S C 26 H 37 NO 5 443.6 444.2 96 3.06 11-3 R / S C 27 H 39 NO 5 457.6 458
  • Table 2 presents steroids made using the methods described herein. Table 2 - Structure and Chemical-Physical Properties of Compounds Cpd. No Structure MF MS (m/z) 100% Highes t m/z peak HPLC purity (%) 4b C 25 H 33 F 2 NO 5 .
  • Table 4 below presents linker payloads made using the methods described herein. Table 4. Examples of Linker-Payloads Structure LP101 LP102 LP103 LP104 LP105 LP108 LP110 LP112 LP113 LP114 LP115 LP116
  • This example demonstrates methods for making chemical derivatives of budesonide, dexamethasone, and flumethasone. These methods are illustrated, generally, as shown in FIGs. 2 , 3 , and 4 .
  • mesylate analogs of Budesonide ( 9 ) or its difluoro-analog ( 9B ) were reacted with alkyl amines or substituted phenols ( 10 ) to yield aniline- or amine-including compounds ( 11 ), such as compounds 11-1 to 11-23 in FIG. 2 .
  • stereochemically pure epimers of 11 - 5 S and 11-5 R in Table 1 were obtained by chiral separation from a mixture of their corresponding R / S isomers.
  • the absolute stereochemistry for each compound was determined by 2D-NOESY.
  • the 2D-NOESY spectra showed that H 22 and H 18 were correlated in 11-5 R , and that there was no correlation between H 22 and H 18 in 11-5 S.
  • the chiral centers at C 22 -position were identified for compounds 7-1 S , 7-1 R , 7-4 R , 8-1 R , 11-6 S , 11-6 R , 11-7 R , 11-8 R , 11-12 R , 11-13 R , and 11-19 R in Table 1 by 2D-NOESY.
  • This example demonstrates a method for making compounds 7-1 S and 7-1 R in Table 1. This example refers to the compounds numbered in FIG. 1 .
  • Step 1 Compound 3 was synthesized according to the procedures in US2007/135398 , the entire contents of which are herein incorporated by reference in its entirety for all purpose, by reacting desonide ( 1 ) with isobutyric acid in acetone.
  • Step 2 To a solution of compound 3 (320 mg, 0.657 mmol) in nitropropane (20 mL) was added aqueous perchloric acid (70%, 1.90 g, 1.33 mmol) dropwise at 0°C, followed by the addition of 4-nitrobenzaldehyde ( 4-1 , 151 mg, 1.00 mmol). The resulting mixture was stirred at RT overnight, and was then diluted with ethyl acetate (80 mL). The resulting mixture was washed with saturated aqueous sodium bicarbonate solution (30 mL x 3) and then brine (30 mL x 2). The resulting solution was then dried over sodium sulfate and concentrated in vacuo.
  • aqueous perchloric acid 70%, 1.90 g, 1.33 mmol
  • 4-nitrobenzaldehyde 4-1 , 151 mg, 1.00 mmol
  • Step 3 Making (1S,2S,4R,6R,8S,9S,11S,12S,13R)-6-(4-Aminophenyl)-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-5,7-dioxapentacyclo[10.8.0.0 2,9 .0 4,8 0 13,18 ]icosa-14,17-dien-16-one ( 7-1 R ) in Table 1) and (1 S ,2 S ,4 R ,6 S ,8 S ,9 S ,11 S ,12 S ,13 R )-6-(4-Aminophenyl)-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-5,7-dioxapentacyclo[10.8.0. 0 2,9 .0 4,8 .0 13,18 ]icosa-14,17-dien-16-one ( 7-1 S ) in Table 1).
  • This example demonstrates a method for making compounds ( 8-1 R / S ) and compound ( 8-1 R ) in Table 1. This example refers to the compound numbering in FIG. 1 .
  • the R -epimer was further isolated and the configuration was determined by 2D NMR.
  • This example demonstrates a method for making compound ( 7-2 R / S ) in Table 1. This example refers to the compound numbering in FIG. 1 .
  • Step 1 1 S ,2 S ,4 R ,8 S ,9 S ,11 S ,12 S ,13 R )-11-Hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-[(4-nitrophenyl)methyl]-5,7-dioxapentacyclo[10.8.0.0 2,9 .0 4,8 .0 13,18 ]icosa-14,17-dien-16-one ( 5-2 ).
  • Step 2 (1 S ,2 S ,4 R ,8 S ,9 S ,11 S ,12 S ,13 R )-6-[(4-Aminophenyl)methyl]-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-5,7-dioxapentacyclo[10.8.0.0 2,9 .0 4,8 .0 13,18 ]icosa-14,17-dien-16-one ( 7-2 R / S )
  • Iron powder (78.0 mg, 1.40 mmol) and ammonium chloride (75.0 mg, 1.40 mmol) were simultaneously added to a solution of compound ( 5-2 ) (75.0 mg, 0.143 mmol) in a combined solution of ethanol (4 mL) and water (0.5 mL).
  • the suspension was stirred at 80°C for 1.5 hours and was filtered through Celite to remove the solid.
  • the filtrate was concentrated in vacuo and the residue was purified by prep-HPLC (method B) to yield compound ( 7-2 R / S ) (26 mg, yield 37%) as a white solid.
  • This example demonstrates a method for making compound ( 8-2 R / S ) in Table 1. This example refers to the compound numbering in FIG. 1 .
  • Step 1 2-[(1S,2S,4R,8S,9S,11S,12S,13R)-11-Hydroxy-9,13-dimethyl-6-[(4-nitrophenyl)methyl]-16-oxo-5,7-dioxapentacyclo[10.8.0.0 2,9 .0 4,8 .0 13,18 ]icosa-14,17-dien-8-yl]-2-oxoethyl 2-methylpropanoate ( 6-2 )
  • Step 2 2-[(1S,2S,4R,8S,9S,11S,12S,13R)-6-[(4-Aminophenyl)methyl]-11-hydroxy-9,13-dimethyl-16-oxo-5,7-dioxapentacyclo[10.8.0.0 2,9 .0 4,8 .0 13,18 ]icosa-14,17-dien-8-yl]-2-oxoethyl 2-methylpropanoate ( 8-2 R / S )
  • This example demonstrates a method for making compound ( 8-3 R / S ) in Table 1. This example refers to the compound numbering in FIG. 1 .
  • Step 1 2-[(1 S ,2 S ,4 R ,8 S ,9 S ,11 S ,12 S ,13 R )-6-(2- ⁇ [(9 H -Fluoren-9-ylmethoxy)carbonyl]amino ⁇ ethyl)-11-hydroxy-9,13-dimethyl-16-oxo-5,7-dioxapentacyclo[1 0.8.0.0 2,9 .0 4,8 .0 13,18 ]icosa-14,17-dien-8-yl]-2-oxoethyl 2-methylpropanoate ( 6-3 )
  • Step 2 2-[(1 S ,2 S ,4 R ,8 S ,9 S ,11 S ,12 S ,13 R )-6-(2-Aminoethyl)-11-hydroxy-9,13-dimethyl-16-oxo-5,7-dioxapentacyclo[10.8.0.0 2,9 .0 4,8 .0 13,18 ]icosa-14,17-dien-8-yl]-2-oxoethyl 2-methylpropanoate ( 8-3 R / S )
  • This example demonstrates a method for making compound 7-4 R in Table 1. This example refers to the compound numbering in FIG. 1 .
  • This example demonstrates a method for making compound ( 11-1 R / S ) in Table 1. The method is illustrated, generally, as shown in FIG. 2 .
  • Step 1 2-[(1 S ,2 S ,4 R ,8 S ,9 S ,11 S ,12 S ,13 R )-11-Hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-dioxapentacyclo[10.8.00 2,9 .0 4,8 .0 13,18 ]icosa-14,17-dien-8-yl]-2-oxoethyl methanesulfonate ( 9 )
  • Step 2 (1 S ,2 S ,4 R ,8 S ,9 S ,11 S ,12 S ,13 R )-8-(2-Aminoacetyl)-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentacyclo[10.8.0.0 2,9 .0 4,8 .0 13,18 ]icosa-14,17-dien-16-one ( 11-1 R / S )
  • This example demonstrates a method for making compound 11-2 R / S in Table 1. This example refers to the compound numbering in FIG. 2 .
  • This example demonstrates a method for making compound 11-3 R / S in Table 1. This example refers to the compound numbering in FIG. 2 .
  • This example demonstrates a method for making compound 11-5 R / S in Table 1. This example refers to the compound numbering in FIG. 2 .
  • Step 1 A mixture of compound 9 (0.13 g, 0.26 mmol), 4-nitrophenol ( 10-5 , 72 mg, 0.52 mmol) and potassium carbonate (72 mg, 0.52 mmol) in acetone (10 mL) was refluxed (60 °C) overnight. After filtration to remove the solids, the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (0-1% methanol in methylene chloride) to yield a nitro-intermediate (0.11 g, yield 77%) as brown oil. ESI m/z: 552 (M + H) + .
  • Step 2 Iron powder (0.10 g, 1.9 mmol) and ammonium chloride (0.10 g, 1.9 mmol) were simultaneously added to a solution of the nitro-intermediate (0.10 g, 0.19 mmol) in a combined solution of ethanol (20 mL) and water (2 mL). The suspension was stirred at 80°C for 2 hours and was filtered through Celite to remove inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by prep-HPLC (method B) to yield compound ( 11-5 R / S ) (50 mg, yield 50%) as a white solid. ESI m/z: 522 (M + H) + .
  • This example demonstrates a method for making compounds 11-5 S and (11-5 R ) in Table 1. This example refers to the compound numbering in FIG. 2 .
  • Compound 9 R was prepared from ( R )-budesonide and compound 9 S was prepared from (S)-Budesonide, respectively, according to the General procedure A in Example 9.
  • compound ( 11-5 S ) was obtained from the reaction of compound ( 9 S ) with compound ( 10 - 12 ), and compound ( 11-5 R ) was obtained from the reaction of compound ( 9 R ) with compound ( 10 - 9 ), respectively.
  • a representative procedure is following. To a solution of compound ( 9 R ) or compound ( 9 S (100 mg) in acetone (10 mL) was simultaneously added compound 10-9 (2eq.) and Cs 2 CO 3 (2eq.).
  • This example demonstrates a method for making compound 11-6 S and 11-6 R from Table 1. This example refers to the compound numbering in FIG. 2 .
  • a racemic mixture of compounds 11-6R/S were prepared according to the method set forth in Example 12. The racemic products were separated by chiral SFC (see details in Section 2.3) to yield compound 11-6 S (second peak) and compound 11-6 R (first peak) as off-white solids.
  • This example demonstrates a method for making compound 11-7 R in Table 1. This example refers to the compound numbering in FIG. 2 .
  • a racemic mixture of steroids 11-7-22R/S were prepared according to the method set forth in Example 12. The racemic products were separated by chiral SFC (see details in Section 2.3) to yield compound 11-7 S (second peak) and compound 11-7 R (first peak).
  • This example demonstrates a method for making compound 11-8 R in Table 1. This example refers to the compound numbering in FIG. 2 .
  • Steroid 11-8 was prepared according to the method set forth in Example 13.
  • This Example demonstrates a method for making compound ( 11-10 R / S ), in Table 1. This example refers to the compound numbering in FIG. 2 .
  • Steroids 11-10 R / S were prepared according to the method set forth in Example 13.
  • This Example demonstrates a method for making compound 11-11 R / S in Table 1. This example refers to the compound numbering in FIG. 2 .
  • Steroids 11-11 R / S were prepared according to the method set forth in Example 13.
  • This Example demonstrates a method for making compounds 11-12 R / S in Table 1. This example refers to the compound numbering in FIG. 2 .
  • Step 1 Compound ( 9B ) was prepared according to the General procedure A in Example 9. To a solution of (6S,9R)2F-budesonide (80 mg, 0.17 mmol) in DCM (1 mL) were added dropwise triethylamine (34 mg, 0.34 mmol) and methanesulfonyl chloride (30 mg, 0.26 mmol) at 0 °C. The mixture was stirred at this temperature for half an hour until (6S,9R)2F-Budesonide was consumed, which was monitored by TLC. The reaction mixture was then diluted with DCM (100 mL) and quenched with sat. aq. ammonium chloride (30 mL). The organic solution was washed with sat. aq. ammonium chloride and brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (0-2% MeOH in DCM) to give the corresponding mesylate product ( 9B ).
  • Step 2 Compound 9B was dissolved in acetone (0.5 mL). To the solution were added 4-aminophenol ( 10-9 , 37 mg, 0.34 mmol) and cesium carbonate (0.11 g, 0.34 mmol). The reaction mixture was refluxed for 1.5 hours or until ( 9B ) was totally consumed according to TLC and LCMS. The mixture was then diluted with ethyl acetate and filtered. The filtrate was concentrated in vacuo and the residue was purified by prep-HPLC (method B) to give compounds 11-12 R / S (6.0 mg, 6.3% yield from (6S,9R)2F-Budesonide) as a white solid. ESI m/z: 558 (M + H) + .
  • Compound 9B R was prepared according to the General procedure A in Example 9.
  • This Example demonstrates a method for making compound 11-13 R in Table 1. This example refers to the compound numbering in FIG. 2 .
  • Steroid 11-13 R was prepared according to the method set forth in Example 19.
  • This Example demonstrates a method for making compounds 11-14 R / S in Table 1. This example refers to the compound numbering in FIG. 2 .
  • This Example demonstrates a method for making compounds 11-15 R / S in Table 1. This example refers to the compound numbering in FIG. 2 .
  • Step 1 To a solution of 4-(aminomethyl)phenol (1.2 g, 10 mmol) in methanol (70 mL) and water (5 mL) was added Boc 2 O (2.4 g, 11 mmol) dropwise by syringe at RT. The resulting mixture was stirred at RT for an hour until 4-(aminomethyl)phenol was totally consumed, which was monitored by LCMS and TLC. The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate (150 mL). The solution was washed with sat. aq.
  • Step 2 Compound (N-Boc- 11-15 R / S ) was prepared according to the method set forth in Example 19.
  • This Example demonstrates a method for making compounds 11-16 R / S in Table 1. This example refers to the compound numbering in FIG. 2 .
  • This Example demonstrates a method for making compounds 11-17 R / S in Table 1. This example refers to the compound numbering in FIG. 2 .
  • This Example demonstrates a method for making compound 11-19 in Table 1. This example refers to the compound numbering in FIG. 2 .
  • Step 1 A suspension of compound 9B (1.0 g, 1.8 mmol), sodium azide (1.2 g, 18 mmol) in acetone (15 mL) was stirred at 50 °C overnight, when the reaction was completed according to LCMS. After cooled, the reaction mixture was poured into cold water (80 mL). The aqueous mixture was extracted with ethyl acetate (50 mL x 3). The combined organic solution was washed by brine (30 mL), dried over sodium sulfate and concentrated in vacuo to afford crude compound azido precursor of (11-19 R / S ) (0.90 g, > 99% yield) as a yellow solid, which was used for the next step without further purification. ESI m/z: 492 (M + H) + .
  • Step 2 To a solution of the precursor of compounds 11-19 R / S (0.85 g, 1.7 mmol) in THF (20 mL) was added aq. hydrochloride (1 N, 10 mL). The mixture was stirred at 28-32 °C until it turned clear, to which was then added triphenylphosphine (0.68 g, 2.6 mmol) at this temperature. The resulting yellow clear solution was stirred at 28-32 °C for 18 hours, when the reaction was completed according to TLC and LCMS. The mixture was concentrated under vacuum and the residue was purified by reversed phase flash chromatography (0-50% acetonitrile in aq.
  • Step 1 Using the same procedure described above, the azido precursor of (11-19 R ) (0.12 g, 87% yield) was obtained from compound ( 9B R ) as a white solid after purification by flash chromatography (0-50% ethyl acetate in petroleum ether). ESI m/z: 492 (M + H) + .
  • Step 2 Using the same procedure described above, compound 11-19 R (30 mg, 66% yield) was obtained as a white solid after purification by prep-HPLC (method A). ESI m/z: 466 (M + H) + .
  • This Example demonstrates a method for making compound 11-20 R / S in Table 1. This example refers to the compound numbering in FIG. 2 .
  • This Example demonstrates a method for making compounds 11-21 R / S in Table 1. This example refers to the compound numbering in FIG. 2 .
  • This example demonstrates a method for making compound 14-2 in Table 1. This example refers to the compound numbering in FIG. 3 .
  • This example demonstrates a method for making compound 15-5 Table 1. This example refers to the compound numbering in FIG. 3 .
  • Step 1 A mixture of compound ( 12 ) (0.16 g, 0.33 mmol), 4-nitrophenol ( 10-5 , 92 mg, 0.67 mmol) and potassium carbonate (92 mg, 0.67 mmol) in acetone (15 mL) was refluxed (60°C) for 18 hours. After cooled down to RT, the volatiles were removed in vacuo. The residue was purified by flash chromatography (0-1% ethyl acetate in petroleum ether) to yield a nitro-intermediate (0.14 g, yield 79%) as a white solid.
  • Step 2 To a solution of the nitro-intermediate (0.13 g, 0.25 mmol) in a combined solution of ethanol (20 mL) and water (2 mL) was added iron powder (0.14 g, 2.5 mmol) and then ammonium chloride (0.14 g, 2.5 mmol). After stirring at 80 °C for 2 hours, the suspension was cooled down to RT and filtered through Celite to remove the inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by prep-HPLC (method B) to yield compound 15-5 (90 mg, yield 70%) as a white solid. ESI m/z: 502 (M + H) + .
  • This example demonstrates a method for making compound 16-5 in Table 1. This example refers to the compound numbering in FIG. 4 .
  • This example demonstrates methods for separating stereoisomers of certain compounds disclosed herein.
  • SFC Supercritical fluid chromatography
  • SFC used supercritical fluid carbon dioxide as a mobile phase and organic polymer bonded solid adsorbent as a stationary phase. Based on different partition coefficient of the epimers in the two phases, the mixed epimers could be separated by adjusting the mobile phase's density.
  • the structures of 22 R / S -Budesonide were determined stereospecifically by 2D-NOESY. Compared with reported proton NMR data of 22 R / S -Budesonide, the first compound from the chiral SFC was determined to be the R -epimer, while the second was determined to be the S epimer.
  • This example demonstrates methods for making linkers and linker-payloads, generally.
  • R' is a steroid amine or aniline
  • R" is an alkyne containing moiety, such as fragment A or B, or a maleimide moiety, such as C
  • R 1 is an amino-acid residue
  • P is a protective group, such as Fmoc or Boc
  • n is an integer from 0-11
  • m is an integer from 2-4
  • p is an integer from 0-5.
  • the amine ( 23 ) was then coupled with an acid or its active ester ( 24 ), such as V-5, V-7, V in FIG. 10 , VI-8 and VI in FIG. 11 , and VII in FIG. 12 , to generate the linker-payloads ( 25 ).
  • Approach II forms an amide ( 28 ) from a coupling reaction between an acid or its active ester ( 26 ) and VC-pAB ( 27 ) followed by N-deprotection.
  • Compound 28 was then converted to its PNP derivative that further reacted with 21 to generate the linker-payload carbamate ( 29 ).
  • Approach III forms a carbamate ( 30 ) from N-protected-dipeptide-pAB-PNP ( 19 ) and the steroid amine or aniline ( 21 ), followed by N-deprotection; the amine moiety in 30 was then coupled with an acid or its active ester ( 26 ) to generate 29.
  • This example demonstrates methods for making linker DIBAC-Suc-NHS ( V ).
  • the following Example refers to FIG. 10 .
  • Step 1 N -[Tricyclo[9.4.0.0 3,8 ]pentadeca-1(11),3,5,7,9,12,14-heptaen-2-ylidene]hydroxylamine (V-2): A mixture of dibenzosuberenone ( V-1 ) (21 g, 0.10 mol) and hydroxylamine hydrochloride (9.3 g, 0.14 mol) in a combined solution of absolute ethanol (100 mL) and pyridine (200 mL) was stirred and refluxed for 15 hours. TLC showed the starting material was consumed (TLC: 5% methanol in methylene chloride).
  • Step 2 2-Azatricyclo[10.4.0.0 4-9 ]hexadeca-1(16),4(9),5,7,10,12,14-heptene (V-3): To a solution of the oxime ( V-2 ) (5.5 g, 25 mmol) in dry methylene chloride (herein also dichloromethane or DCM) (150 mL) at -5 °C was added DIBAL-H (1 M in toluene, 250 mL) dropwise while maintaining the temperature below -5 °C. The reaction was then stirred at RT overnight and was subsequently quenched with a solution of sodium fluoride solid (38 g, 0.90 mol) in water (12 mL) at 0 °C.
  • DCM dry methylene chloride
  • Step 3 4-[2-Azatricyclo[10.4.0.0 4,9 ]hexadeca-1 (16),4(9),5,7,10,12,14-heptaen-2-yl]-4-oxobutanoic acid (V-5): To a solution of ( V-3 ) (5.0 g, 24 mmol) in methylene chloride (50 mL) were added DIPEA (3.1 g, 24 mmol) and then succinic anhydride ( V-4 , 2.9 g, 29 mmol). The mixture was then stirred at RT for 4 hours, quenched with aq. sodium bisulfate (1N, 100 mL), and extracted with methylene chloride (3 x 100 mL).
  • Step 4 4- ⁇ 10,11-dibromo-2-azatricyclo[10.4.0.0 4,9 ]hexadeca-1(16),4(9),5,7,12,14-hexaen-2-yl ⁇ -4-oxobutanoic acid (V-6): A solution of ( V-5 ) (15 g, 49 mmol) in methylene chloride (200 mL) was flushed with nitrogen and cooled to 0 °C. To the solution was added liquid bromine (23 g, 0.14 mol) dropwise at 0 ° C via a syringe. The reaction was stirred at this temperature for 2 hours and TLC showed the reaction was completed (TLC: 10% methanol in methylene chloride).
  • Step 5 4- ⁇ 2-Azatricyclo[10.4.0.0 4,9 ]hexadeca-1(16),4(9),5,7,12,14-hexaen-10-yn-2-yl ⁇ -4-oxobutanoic acid (V-7): A solution of ( V-6 ) (5.0 g, 11 mmol) in anhydrous THF (50 mL) was cooled to -40 °C with a dry-ice/acetonitrile bath and to the solution was added a solution of potassium tert -butanolate in tetrahydrofuran (1N, 37 mL, 37 mmol) dropwise under argon atmosphere. The reaction mixture was stirred at this temperature for half an hour after the addition.
  • Step 6 4- ⁇ 2-Azatricyclo[10.4.0.0 4,9 ]hexadeca-1(12),4(9),5,7,13,15-hexaen-10-yn-2-yl ⁇ -4-oxobutanoic acid (V): To a solution of acid ( V-7 ) (50 mg, 0.16 mmol) in methylene chloride (10 mL) were subsequently added N -hydroxysuccinimide (HOSu, 28 mg, 0.24 mmol) and N -(3-dimethylaminopropyl)- N '-ethylcarbodiimide hydrochloride (EDCI, 47 mg, 0.24 mmol).
  • N -hydroxysuccinimide HOSu, 28 mg, 0.24 mmol
  • EDCI N -(3-dimethylaminopropyl)- N '-ethylcarbodiimide hydrochloride
  • This example demonstrates methods for making linker DIBAC-Suc-PEG 4 -acid/NHS ( VI ).
  • the following Example refers to FIG. 11 .
  • Step 1 Tert-butyl-1-hydroxy-3,6,9,12-tetraoxapentadecan-15-oate (VI-3): To a solution of tetraethylene glycol ( VI-1 , 58 g, 0.30 mol) in dry THF (200 mL) was added sodium (0.12 g), and the mixture was stirred until the sodium was consumed. To the resulting solution was then added tert -butyl acrylate ( VI-2, 13 g, 0.10 mol) in dry THF (50 mL) dropwise, and the resulting mixture was stirred at RT overnight.
  • VI-3 tetraethylene glycol
  • VI-2 tert -butyl acrylate
  • Step 2 tert -Butyl 1-(methanesulfonyloxy)-3,6,9,12-tetraoxapentadecan-15-oate (VI-4): To a solution of ( VI-3 ) (26 g, 81 mmol), triethylamine (12 mL, 89 mmol) in methylene chloride (150 mL) in an ice-water bath was added a solution of methanesulfonyl chloride (10 g, 89 mmol) in DCM (50 mL) dropwise. The mixture was stirred at RT for 14 hours, and was then concentrated in vacuo.
  • Step 3 tert -Butyl 1-azido-3,6,9,12-tetraoxapentadecan-15-oate (VI-5): To a solution of ( VI-4 ) (27 g, 67 mmol) in DMF (70 mL) was added sodium azide (6.6 g, 0.10 mol), which was then stirred at 80 °C for 4-16 hours. After cooled to RT, the mixture was diluted with ethyl acetate (3 x 150 mL). The combined solution was washed with water (30 mL) and then brine (3 x 100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.
  • Step 4 tert -Butyl 1-amino-3,6,9,12-tetraoxapentadecan-15-oate (VI-6): To a solution of ( VI-5 ) (1.5 g, 4.3 mmol) in ethyl acetate (20 mL) was added wet Pd/C (10%, 0.15 g) under nitrogen. The mixture was then flushed with hydrogen and stirred at RT under a hydrogen balloon overnight. The mixture was then filtered through Celite. The Celite was washed with ethyl acetate (10 mL). The combined filtrate was concentrated in vacuo to yield crude ( VI-6 ) (1.4 g) as light a yellow oil, which was used on the next step without further purification. ESI m/z: 322 (M + H) + .
  • Step 5 1-Amino-3,6,9,12-tetraoxapentadecan-15-oic acid (VI-7): To a solution of ( VI-6 ), obtained above (1.4 g) in methylene chloride (10 mL) was added TFA (5 mL). The mixture was stirred at RT for an hour. The volatiles were removed in vacuo to yield crude product ( VI-7 ) as its TFA salt (1.6 g) as yellow oil, which was used for the next step without further purification. ESI m/z: 266 (M + H) + .
  • Step 6 1-(4- ⁇ 2-Azatricyclo[10.4.0.0 4-9 ]hexadeca-1(12),4(9),5,7,13,15-hexane-10-yn-2-yl ⁇ -4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-oic acid (VI-8): A mixture of 4- ⁇ 2-Azatricyclo[10.4.0.0 4,9 ]hexadeca-l(12),4(9),5,7,13,15-hexaen-1 0-yn-2-yl ⁇ -4-oxobutanoic acid (V in FIG.
  • Step 7 2,5-Dioxopyrrolidin-1-yl 1-(4- ⁇ 2-azatricyclo[10.4.0.0 4-9 ]hexadeca-1(12),4(9),5,7,13,15-hexane-10-yn-2-yl ⁇ -4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-oate (VI): To a solution of ( VI-8) (40 mg, 72 ⁇ mol) in methylene chloride (10 mL) was subsequently added HOSu (1-hydroxypyrrolidine-2,5-dione, 12 mg, 0.11 mmol) and EDCI (21 mg, 0.11 mmol).
  • This example demonstrates methods for making 1-((1 R ,8 S ,9 s )-Bicyclo[6.1.0]non-4-yn-9-yl)-3-oxo-2,7,10,13,16-pentaoxa-4-azanonadecan-19-oic acid ( BCN-PEG 4 -Acid, VII).
  • BCN-PEG 4 -Acid, VII BCN-PEG 4 -Acid, VII.
  • This example demonstrates methods for making ⁇ 4-[(2S)-2-[(2S)-2-[1-(4- ⁇ 2-azatricyclo[10.4.0.0 4,9 ]hexadeca-1(12),4(9),5,7,13,15-hexaen-10-yn-2-yl ⁇ -4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-methylbutanamido]-5-(carbamoylamino)pentanamido]phenyl ⁇ methyl 4-nitrophenyl carbonate (DIBAC-Suc-PEG 4 -VC-pAB-PNP, VIII ).
  • DIBAC-Suc-PEG 4 -VC-pAB-PNP, VIII 4-nitrophenyl carbonate
  • Step 1 To a solution of compound ( VIII-1 ) (300 mg, 0.54 mmol) and compound ( VIII-2, 205 mg, 0.54 mmol) in DMF (10 ml) were added HATU (309 mg, 0.81 mmol) and then DIEA (140 mg, 1.08 mmol). The mixture was stirred at RT for 3 hours. After filtering to remove the insoluble solid and concentrated in vacuo, the reaction mixture was directly purified by reverse flash (NH 4 HCO 3 as buffer), and a white solid ( VIII-3 ) (300 mg, 60%) was obtained. ESI m/z: 617(M+1).
  • Step 2 To a solution of ( VIII-3) (150 mg, 0.16 mmol) and ( VIII-4) (150 mg, 0.49 mmol) in DMF (10 mL) was added DIEA (63 mg, 0.49 mmol). The mixture was stirred at RT for 3 hours. After filtered to remove the insoluble solid and concentrated in vacuo, the reaction mixture was directly purified by reverse flash chromatography (NH 4 HCO 3 as buffer), and ( VIII) as a yellow solid (50 mg, 28%) was obtained. ESI m/z: 1079 (M+1).
  • This example demonstrates methods for making Linker-Payload ( LP1 ).
  • the following Example refers to FIG. 14 .
  • Step 1 A mixture of Boc-Ala-OH (0.20 g, 0.42 mmol), DIPEA (0.12 g, 0.84 mmol) and HATU (0.24 g, 0.63 mmol) in DMF (5 mL) was stirred at 23 °C for 30 minutes. To the solution was then added compound 7-1 R (87 mg, 0.46 mmol). After stirring at 23 °C for another 2 hours, the mixture was directly purified by prep-HPLC (method B) to yield compound 31 (0.11 g, 40% yield) as a white solid. ESI m/z: 651 (M + H) + .
  • Step 2 To a solution of compound 31 (0.10 g, 0.15 mmol) in methylene chloride (3 mL) was added TFA (0.3 mL) dropwise. The mixture was stirred at 23 °C for an hour, and the volatiles were removed in vacuo to yield crude ( 32) (83 mg) as an oil, which was used next step without further purification.
  • Step 3 A mixture of ( 32) (83 mg, 0.15 mmol), triethylamine (31 mg, 0.31 mmol) and Boc-Val-NHS (58 mg, 0.19 mmol) in DMF (5 mL) was stirred 23 °C for 4 hours and the reaction mixture was directly purified by prep-HPLC (method B) to yield (33) (52 mg, 20% yield in 2 steps) as a white solid.
  • Step 4 To a solution of compound 33 (50 mg, 67 ⁇ mol) in methylene chloride (3 mL) was added TFA (0.3 mL) dropwise, which was then stirred at 23 °C for an hour. The volatiles were removed in vacuo to yield crude compound 34g (42 mg) as an oil, which was used the next step without further purification.
  • Step 5 A solution of DIBAC-suc-PEG 4 -OH ( VI-8 , 41 mg, 74 ⁇ mol), DIPEA (24 mg, 0.19 mmol) and HATU (47 mg, 0.12 mmol) in DMF (5 mL) was stirred at 23 °C for 30 minutes, and then ( 34g) (40 mg, 62 ⁇ mol) was added. After being stirred at 23 °C for another 2 hours, the reaction mixture was directly purified by prep-HPLC (method B) to yield LP1 (33 mg, 44% yield in 2 steps) as a white solid. ESI m/z: 1185 (M + H) + .
  • the example demonstrates a method for making Linker-Payload ( LP2 ).
  • the following Example refers to FIG 15 .
  • Step 1 To a solution of Boc-VC (VC is Val-Cit) (67 mg, 0.18 mmol) in DMF (3 mL) were added HATU (68 mg, 0.18 mmol) and NMM (30 mg, 0.30 mmol), and the resulting solution was stirred at 23 °C for 10 minutes. To the reaction mixture was then added compound 15-5 (75 mg, 0.15 mmol). After stirring at 23 °C overnight, the reaction mixture was poured into ethyl acetate (80 mL), washed with brine, and then dried over anhydrous sodium sulfate.
  • Boc-VC VC is Val-Cit
  • NMM 30 mg, 0.30 mmol
  • Step 2 To a solution of intermediate compound 34e (25 mg, 29 ⁇ mol) in methylene chloride (2 mL) was added TFA (1 mL), and the resulting mixture was stirred at 23 °C for an hour. The volatiles were removed in vacuo to yield a residue (25 mg, ESI m/z: 758.3 (M + H) + ) as brown oil residue.
  • the example demonstrates a method for making Linker-Payload ( LP3 ).
  • the following Example refers to FIG. 15 .
  • Step 1 To a solution of payload an aniline (1.0 equiv.) in DMF were added Fmoc-vcPAB-PNP (1.1 equiv.), HOBt (1.5 equiv.) and DIPEA (2.0 equiv.) at RT. The mixture was stirred at RT (18-30 °C) until the starting material was consumed according to LCMS.
  • Step 2 To the reaction mixture was added piperidine (0.03 mL per 10 mg of payload) and the mixture was stirred at RT (18-30 °C) for an hour until Fmoc was removed monitored by LCMS. After filtered through membrane, the reaction solution was directly purified by reversed phase flash chromatography or prep-HPLC to generate the vcPAB carbonate.
  • N -Boc-vcPAB-PNP When N -Boc-vcPAB-PNP was used to replace Fmoc-vcPAB-PNP in the Step 1 reaction, the N -Boc vcPAB carbonate was obtained from Step 1. After purification, the N -Boc vcPAB carbonate was redissolved in DCM, and was treated with TFA (TFA concentration ⁇ 25%) at 0 °C until the Boc was removed monitored by LCMS. The reaction mixture was concentrated to remove the volatiles and the resulting residue was purified by chromatography or prep-HPLC to generate the vcPAB carbonate.
  • TFA TFA
  • Step 3 To a solution of BCN-PEG 4 -acid (60 mg, 67 ⁇ mol) in DMF (3.6 mL) were added HATU (27 mg, 70 ⁇ mol) and DIPEA (20 mg, 0.15 mmol) successively at RT. The reaction mixture was stirred at RT for half an hour followed by the addition of compound ( 34f ) (50 mg, 60 ⁇ mol) portionwise. The reaction mixture was then stirred at RT for 2 hours until compound 34f was totally consumed according to LCMS. The reaction mixture was then directly purified by prep-HPLC (method B) to yield compound LP3 (36 mg, yield 54%) as a white solid . ESI: 1330 (M + H) + .
  • the example demonstrates a method for making Linker-Payload ( LP4 ).
  • the following Example refers to FIG. 16 .
  • reaction solution was directly purified by reversed phase flash chromatography (0-100% acetonitrile in aq. ammonium bicarbonate (10 mM)) or prep-HPLC (method B).
  • Red phase flash chromatography (0-100% acetonitrile in aq. ammonium bicarbonate (10 mM)
  • prep-HPLC prep-HPLC
  • the example demonstrates a method for making Linker-Payload ( LP5 ).
  • the following Example refers to FIG.16 .
  • LP5 was obtained following the General procedure F.
  • a solution of BCN-PEG4-acid ( IX in FIG. 15 , 0.28 g) in methylene chloride (6 mL) was added to a mixture of HATU (59 mg, 0.15 mmol) and DIPEA (50 mg, 0.39 mmol) in DMF (5 mL).
  • the reaction mixture was stirred at 25 °C for 30 minutes and to it was added compound 34c (0.10 g, 0.13 mmol) in one portion.
  • the resulting mixture was stirred at 25 °C overnight and was directly purified by prep-HPLC (method B) to yield LP5 (35 mg, 23% yield) as a pale yellow solid.
  • the example demonstrates a method for making Linker-Payload ( LP6 ).
  • the following Example refers to FIG. 16 .
  • Step 1 To a solution of compound ( 11-5) from Table 1 (66 mg, 0.10 mmol) in DMF (3.5 mL) were added successively Boc-vcPAB-PNP (64 mg, 0.12 mmol), HOBt (14 mg, 0.10 mmol) and DIPEA (13.0 mg, 0.10 mmol). The reaction mixture was stirred at 13 °C overnight and was purified directly by prep-HPLC (method B) to yield intermediate Boc-34d (61 mg, yield 58%) as a white solid.
  • Step 2 To a solution of Boc-34d (59 mg, 58 ⁇ mol) in DCM (2 mL) and MeOH (1 mL) was added dropwise HCl in dioxane (4 N, 1.5 mL) at 0 °C. The mixture was then stirred at RT (14 °C) for 4 hours. The volatiles were removed in vacuo to yield 34d (60 mg, crude) as brown oil, which was used directly for the next step. ESI m/z: 927 (M + H) + .
  • the example demonstrates a method for making Linker-Payload LP7.
  • the following Example refers to FIG. 16 .
  • the example also demonstrates a method for making Linker-Payload ( LP7 ).
  • the following Example refers to FIG. 26 .
  • the following reaction conditions were used: Amine mg ( ⁇ mol) Acid mg ( ⁇ mol) Step 1 mg % Yield MS m/z HATU mg ( ⁇ mol) DIPEA mg ( ⁇ mol) DMF (mL) Temp. (°C) Time (hr) 26 b 30 (43) VI-8 48 (87) 40 (105) 17 (132) 1 25 16 30 56% 1227.6 (M+H) +
  • Solubility ⁇ 0.1 mg/mL water; 0.06 mg/mL 20% DMSO in water; 0.07 mg/mL 30% DMSO in water.
  • This example demonstrates a method for making Linker-Payload ( LP15 ).
  • the following Example refers to FIGs. 27-28 . Note that in FIG. 27 , compound 11b is identical to compound 11-5 in FIG. 2 .
  • Step 1 Making Compound (13b), with reference to FIG. 27.
  • Step 2 Making Compound (17a) , with reference to FIG. 27.
  • Step 3 Making Compound (27b) , with reference to FIG. 27.
  • Step 4 Making Compound (LP15) , with reference to FIG. 28.
  • This example demonstrates a method for making Linker-Payload ( LP16 ).
  • the following Example refers to FIGS. 27-28 .
  • the method for making LP16 was the same as the method for making LP15, in Example 45 herein, except that a different payload was used, as shown in FIGs. 27-28 .
  • the following reaction conditions were used: Amine mg ( ⁇ mol) Acid mg ( ⁇ mol) Step 1 purifi catio n mg % Yield MS m/z HATU mg ( ⁇ mol) DIPEA mg ( ⁇ mol) DMF (mL) Tem p. (°C) Time (hr) 2 7 b 30 (15) VI -8 10 (18) 8.0 (21) 6.0 (47) 1 15-20 16 B 18 47% 1259.1 (M/2+H) +
  • the example demonstrates a method for making Linker-Payload ( LP8 ).
  • the following Example refers to FIG. 16 .
  • the example demonstrates a method for making Linker-Payload ( LP9 ).
  • the following Example refers to FIG. 16 .
  • the example demonstrates a method for making Linker-Payload ( LP10 ).
  • the following Example refers to FIG. 16 .
  • the example demonstrates a method for making Linker-Payload LP11.
  • the following Example refers to FIG. 16 .
  • the example demonstrates a method for making Linker-Payload LP12.
  • the following Example refers to FIG. 17 .
  • Step 1 The synthesis of [(2 R ,3 R ,4 S ,5 R ,6 S )-3,4,5-Tris(acetyloxy)-6-(4-formyl-3-hydroxyphenoxy)oxan-2-yl]methyl acetate ( 43 ) was reported in Carbohydrate Research, 1986, 146, 241-249 , the entire contents of which are herein incorporated by reference in its entirety.
  • Step 2 To a solution of compound 45 (0.83 g, 1.6 mmol) in isopropanol (50 mL) was added sodium borohydride (31 mg, 0.82 mmol). The mixture was stirred at 23°C for 2 hours and was then concentrated in vacuo. The residue was diluted with ethyl acetate and washed with brine. The organic solution was dried over sodium sulfate and concentrated to afford compound 46 (0.70 g, yield 84%) as brown oil.
  • Step 3 To a solution of compound 46 (0.40 g, 0.79 mmol) in methylene chloride (30 mL) were added 4-nitrophenyl carbonochloridate ( 47 , 0.24 g, 1.2 mmol), 4-dimethylaminopyridine (0.19 g, 1.6 mmol) and diisopropylethylamine (0.20 g, 1.6 mmol). The mixture was stirred at 23 °C overnight and diluted with methylene chloride (50 mL). The organic solution was washed with saturated aqueous ammonium chloride solution (50 mL) and then brine (50 mL), dried over sodium sulfate and concentrated.
  • 4-nitrophenyl carbonochloridate 47 , 0.24 g, 1.2 mmol
  • 4-dimethylaminopyridine (0.19 g, 1.6 mmol
  • diisopropylethylamine 0.20 g, 1.6 mmol
  • Step 4 To a solution of compound 48 (0.15 g, 0.22 mmol) in DMF (5 mL) were added 11-5 (0.14 g, 0.26 mmol), HOBt (59 mg, 0.44 mmol) and diisopropylethylamine (57 mg, 0.44 mmol) successively. The mixture was stirred at 23°C overnight and was then purified by prep-HPLC (method B) to yield compound 49 (0.14 g, 62% yield) as a white solid. ESI m/z: 1056.3 (M + H)+.
  • Step 5 To a solution of compound 49 (35 mg, 33 ⁇ mol) in methanol (3 mL) was added another solution of LiOH in H 2 O (14 mg, 0.33 mmol) in water (1 mL). The mixture was stirred at 23 °C for 1.5 hours and was quenched with HOAc (20 mg). The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (method B) to yield linker-payload LP12 (26 mg, 88% yield) as a white solid.
  • the example demonstrates a method for making Linker-Payload LP13.
  • the following Example refers to FIG. 18 .
  • the example demonstrates a method for making Linker-Payload LP14.
  • the following Example refers to FIG. 18 .
  • Table 7 summarizes certain physical properties of LP1-LP16.
  • Table 7 Physical Properties of Certain Linker-Payloads LP No. MF MW Purity (%) MS m/z (100%) Highest m/z HPLC RT (min) LP1 C 66 H 81 N 5 O 15 1184.4 98 593 (M/2+H) 1185 (M+H, 20%) 6.53 (B) LP2 C 61 H 86 F 2 N6O 15 1181.4 100 1181.4 (M+H) 1181.4 (M+H) 7.83 (B) LP3 C 70 H 94 F 2 N 6 O 17 1329.5 100 1330.4 (M+H) 1330.4 (M+H) 7.03 (B) LP4 C 61 H 86 N 4 O 15 1115.4 100 1115 [M+H] 1115 [M+H] 8.17 (A) 8.24 (B) LP5 C 64 H 92 N 6 O 16 1201.5 100 1201 [M+H] 1201 [M+H] 7.34 (
  • This example demonstrates a method for site-specific conjugation, generally, of a payload to an antibody or antigen-binding fragment thereof. This example refers to FIG. 19 .
  • site-specific conjugates were produced via Microbial transglutaminase (MTG EC 2.3.2.13, Zedira, Darmstadt, Germany) (herein "MTG-based") two-step conjugation of an N297Q or N297D mutated antibody.
  • Microbial transglutaminase Microbial transglutaminase (MTG EC 2.3.2.13, Zedira, Darmstadt, Germany)
  • MTG-based Microbial transglutaminase
  • the mutated antibody was functionalized with azido-PEG 3 -amine via MTG based enzymatic reaction. See, e.g. , International PCT Patent Application No. PCT/US17/19537, filed February 24, 2017 , entitled OPTIMIZED TRANSGLUTAMINASE SITE-SPECIFIC ANTIBODY CONJUGATION, incorporated herein by reference in its entirety for all purposes.
  • an alkyne-functionalized linker-payload was attached to the azido-functionalized antibody via [2+3] 1, 3-dipolar cycloaddition reaction (see, e.g. , FIG. 19 , which depicts a DIBAC-functionalized linker-payload conjugated with an azido-functionalized antibody derived via [2+3] cyclization).
  • This process provided site-specific and stoichiometric conjugates in about 50-80% isolated yield.
  • This Example demonstrates specific procedures for site-specific conjugation of an alkyne-linker-payload to antibody.
  • This example refers to the compounds depicted in FIG. 29 .
  • the site-specific conjugates were produced in two steps.
  • the first step is Microbial transglutaminase (MTG)-based enzymatic attachment of a small molecule, such as azide-PEG 3 -amine (supra), to the antibody having a Q-tag (references for the Qtag) (hereinafter "MTG-based" conjugation).
  • the second step employed the attachment of a linker-payload to the azido-functionalized antibody via a [2+3] cycloaddition, for example, the 1,3-dipolar cycloaddition between the azides and the cyclooctynes (aka copper-free click chemistry). See, Baskin, J. M
  • FIG. 28 Shown in FIG. 28 is an example of a linker-payload having a DIBAC moiety conjugated with an azido-functionalized antibody via a [2+3] cycloaddition. This process provided the site-specific and stoichiometric conjugates in about 50-80% isolated yield.
  • Step 1 Preparation of an azido-functionalized antibody.
  • the resulting solution was mixed with MTG (EC 2.3.2.13 from Zedira, Darmstadt, Germany, or Modernist Pantry [L# 210115A] - ACTIVA TI contains Maltodextrin from Ajinomoto, Japan) (25 U/mL; 5U MTG per mg of antibody) resulting in a final concentration of the antibody at 0.5-5 mg/mL, and the solution was then incubated at 37 °C for 4-24 h while gently shaking. The reaction was monitored by ESI-MS. Upon reaction completion, the excess amine and MTG were removed by SEC or protein A column chromatography, to generate the azido-functionalized antibody. This product was characterized by SDS-PAGE and ESI-MS. The azido-dPEG 3 -amine added to two sites of the antibody resulting in a 204 Da increase for the 2DAR antibody-PEG 3 -azide conjugate.
  • MTG EC 2.3.2.13 from Zedira, Darmstadt, Germany, or Modern
  • the N-terminal Q tag antibody 24 mg in 7 mL potassium-free PBS buffer (pH 7.3) was incubated with > 200 molar equivalent of the azido-PEG 3 -amine (MW 218.26) in the presence of MTG (0.350 mL, 35 U, mTGase, Zedira, Darmstadt, Germany). The reaction was incubated at 37 °C overnight while gently mixing. Excess azido-PEG 3 -amine and mTGase were removed by size exclusion chromatography (SEC, Superdex 200 PG, GE Healthcare).
  • Step 2 Preparation of site-specific conjugates of a drug to an antibody using click chemistry reactions.
  • the site-specific antibody drug conjugates with a human IgG (IgG1, IgG4, etc.) in Table 10 were prepared by a [2+3] click reaction between azido-functionalized antibodies and an alkyne containing linker-payload. The detailed conjugation procedure follows.
  • a site-specific antibody conjugate with linker-payload (LP ) was prepared by incubating mAb-PEG 3 -N 3 (1-3 mg / mL) in an aqueous medium (e.g., PBS, PBS containing 5% glycerol, HBS) with ⁇ 6 molar equivalents of an LP dissolved in a suitable organic solvent, such as DMSO, DMF or DMA (i.e., the reaction mixture contains 5-20% organic solvent, v/v) at 24 °C to 37 °C for over 6 h.
  • aqueous medium e.g., PBS, PBS containing 5% glycerol, HBS
  • a suitable organic solvent such as DMSO, DMF or DMA
  • the progress of the reaction was monitored by ESI-MS and the absence of mAb-PEG 3 -N 3 indicated the completion of the conjugation.
  • the excess amount of the LP and organic solvent were removed by SEC via elution with P
  • the azido-functionalized antibody (1 mg) in 0.800 mL PBSg PBS, 5% glycerol, pH 7.4 was treated with six molar equivalents of DIBAC-PEG 4 -D-Lys (COT- ⁇ -CD)-VC-PABC-payload (conc. 10 mg/mL in DMSO) for 6 -12 hours at room temperature and the excess linker payload (LP) was removed by size exclusion chromatography (SEC, Superdex 200 HR, GE Healthcare).
  • the final product was concentrated by ultra centrifugation and characterized by UV, SEC, SDS-PAGE and ESI-MS.
  • This example demonstrates a method for making an azido-functionalized antibody drug conjugate.
  • Aglycosylated antibody with a human IgG1 isotype in BupH TM (pH 7.6-7.8) was mixed with ⁇ 200 molar equivalents of azido-dPEG 3 -amine (MW. 218.26 g/mol).
  • the resulting solution was mixed with transglutaminase (25 U/mL; 5U MTG per mg of antibody, Zedira, Darmstadt, Germany) resulting in a final concentration of the antibody at 0.5-3 mg/mL, and the solution was then incubated at 37 °C for 4-24 hours while gently shaking.
  • the reaction was monitored by SDS-PAGE or ESI-MS. Upon the completion, the excess amine and MTG were removed by Size Exclusion Chromatography (see FIG.
  • This example demonstrates a method for making a site-specific conjugations of a drug to an antibody using click chemistry reactions.
  • the site-specific aglycosylated antibody drug conjugates with an human IgG1 containing an N297Q mutation in Table 8 described below were prepared by a [2+3] click reaction between azido-functionalized antibodies with an alkyne containing linker-payload.
  • Anti Her2-PEG 3 -N 3 was conjugated to compounds LP1, LP2, LP3, LP4, LP5, LP6, LP7, LP8, LP9, LP10, and LP11.
  • Anti PRLR- PEG 3 -N 3 was conjugated to LP1 LP2, LP3, LP4, LP5, LP6, LP7, LP8, LP9, LP10, LP11, LP15, and LP16.
  • Anti-IL2Rg-PEG 3 -N 3 was conjugated to LP4 and LP7.
  • Anti-Fel d 1-PEG 3 -N 3 was conjugated to LP4.
  • an azido-functionalized aglycosylated human IgG1 antibody ( mAb-PEG 3 -N 3 ) and linker-payload ( LP ) conjugate was prepared by incubating mAb-PEG 3 -N 3 (1-3 mg / mL) in an aqueous medium (e.g., PBS, PBS containing 5% glycerol, HBS) with ⁇ 6 molar equivalent of an LP dissolved in a suitable organic solvent, such as DMSO, DMF or DMA (reaction mixture contains 10 - 20% organic solvent, v/v) at 24°C to 37°C for over 6 hours. The progress of the reaction was monitored by ESI-MS.
  • an aqueous medium e.g., PBS, PBS containing 5% glycerol, HBS
  • a suitable organic solvent such as DMSO, DMF or DMA
  • ncADCs non-toxic steroid antibody conjugates
  • This example demonstrates a method for making a non-site-specific conjugation of a drug to an antibody using a thiol-maleimide reaction.
  • a monoclonal antibody (mAb, 10 mg/ml in 50 mM HEPES, 150 mM NaCl) at pH 7.5 was reduced with 1 mM dithiothreitol (0.006 mg per mg of antibody) or TCEP (2.5 molar equivalent to antibody) at 37 °C for 30 minutes.
  • compound LP13 in DMSO (10 mg/mL) was added to the reduced antibody, and the mixture was adjusted to pH 7.0 with 1 M HEPES (pH 7.4). The reaction was allowed to react for 3-14 hours.
  • the resulting conjugate was purified by SEC.
  • the DAR (UV) values were determined using the measured absorbances of the ncADC and the extinction coefficients of the antibody and LP13.
  • This example demonstrates methods for characterizing antibody and non-cytotoxic antibody drug conjugates (ncADC).
  • the antibody and ncADC were characterized by SDS-PAGE, SEC, and MS (ESI).
  • the anti-PRLR-LP4 conjugate in Table 8 generated from anti-PRLR antibody via its azido-functionalized antibody (anti-PRLR-PEG 3 -N 3 ) was characterized by SDS-PAGE performed under non-reducing and reducing conditions ( FIG. 20 ), SEC ( FIG. 21 ) and ESI-MS ( FIG. 22 ), and demonstrated completion of the ncADC formation.
  • SDS-PAGE running conditions included non-reduced and reduced samples (2-4 ⁇ g) along with BenchMark Pre-Stained Protein Ladder (Invitrogen, cat# 10748-010; L# 1671922.) were loaded per lane in (1.0 mm x 10 well) Novex 4 - 20% Tris-Glycine Gel and was ran at 180 V, 300 mA, for 80 minutes.
  • An analytic sample was prepared using Novex Tris-Glycine SDS buffer (2X) (Invitrogen, Cat# LC2676) and the reducing sample was prepared with SDS sample buffer (2X) containing 10% 2-mecaptoethanol.
  • FIG. 20 are shown the molecular weights of the antibodies and ncADCs on SDS-PAGE performed under non-reducing and reducing conditions.
  • the mass shifts were not obvious under non-reducing conditions due to relatively small percentages of mass changes.
  • the masses of the heavy chains were increased from the naked antibodies to the azido-functionalized antibodies, and further to the ncADC conjugate. There was no detectable cross-linked material.
  • the SDS-PAGE lanes included the following species based on the following lane labels in Table 9.
  • Table 9 Lane Sample 1 Standards (Bench Mark 10 ⁇ L) 2 anti-PRLR antibody 3 anti-PRLR antibody -NH-PEG 3 -N 3 4 anti-PRLR antibody -LP4 8 anti-PRLR antibody (reduced) 9 anti-PRLR antibody NH-PEG 3 -N 3 (reduced) 10 anti-PRLR antibody -LP4 (reduced) ⁇ 2 ⁇ g of non-reduced/reduced sample/lane.
  • Antibody and ADC were analyzed by intact mass analysis by LC-ESI-MS.
  • Measurement of intact mass of the ncADC samples by LC-ESI-MS was performed to determine drug-payload distribution profile and to calculate the average DAR of intact ADC forms.
  • Each testing sample (20-50 ng, 5uL) was loaded onto an Acquity UPLC Protein BEH C4 column (10K psi, 300 ⁇ , 1.7 ⁇ m, 75 ⁇ m ⁇ 100 mm; Cat No. 186003810). After 3 min desalting, the protein was eluted and mass spectra were acquired by a Waters Synapt G2-Si mass spectrometer (Waters).
  • the deconvoluted mass spectra exhibited a predominant peak for the aglycosylated anti-PRLR antibody with molecular weight of 144579.0 Da, and a predominant peak for its azido functionalized anti-PRLR antibody with molecular weight of 145373.0 Da, indicating a 794.0 Da increase compared to its aglycosylated parent antibody (corresponding to 4 amino-PEG 3 -azide conjugation to each aglycosylated antibody).

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Families Citing this family (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102435599B1 (ko) 2016-06-02 2022-08-29 애브비 인코포레이티드 글루코코르티코이드 수용체 작용제 및 이의 면역접합체
KR102835535B1 (ko) 2016-11-08 2025-07-18 리제너론 파마슈티칼스 인코포레이티드 스테로이드 및 이의 단백질-접합체
CN110944718A (zh) 2017-05-18 2020-03-31 里珍纳龙药品有限公司 环糊精蛋白质药物偶联物
AU2018365946B2 (en) * 2017-11-07 2025-08-28 Regeneron Pharmaceuticals, Inc. Hydrophilic linkers for antibody drug conjugates
RS61994B1 (sr) 2017-12-01 2021-07-30 Abbvie Inc Agonist glukokortikoidnog receptora i njegovi imunokonjugati
MX2020006994A (es) * 2018-01-08 2020-11-06 Regeneron Pharma Esteroides y conjugados de anticuerpos de los mismos.
CN118955710A (zh) 2018-05-09 2024-11-15 里珍纳龙药品有限公司 抗msr1抗体及其使用方法
US12209180B2 (en) * 2018-11-20 2025-01-28 Regeneron Pharmaceuticals, Inc. Bis-octahydrophenanthrene carboxamide derivatives and protein conjugates thereof for use as LXR agonists
CN119264215A (zh) * 2019-01-08 2025-01-07 里珍纳龙药品有限公司 无痕连接体及其蛋白质偶联物
CN115175737A (zh) 2020-02-28 2022-10-11 瑞泽恩制药公司 结合her2的双特异性抗原结合分子及其使用方法
WO2022015656A1 (en) * 2020-07-13 2022-01-20 Regeneron Pharmaceuticals, Inc. Camptothecin analogs conjugated to a glutamine residue in a protein, and their use
CA3190569A1 (en) 2020-10-22 2022-04-28 Christopher Daly Anti-fgfr2 antibodies and methods of use thereof
IL302814A (en) 2020-11-10 2023-07-01 Regeneron Pharma Selenium antibody conjugates
US20240100177A1 (en) * 2020-12-04 2024-03-28 Dyne Therapeutics, Inc. Antibody-oligonucleotide complexes and uses thereof
WO2022135332A1 (zh) * 2020-12-21 2022-06-30 映恩生物制药（苏州）有限公司 一种甾体偶联物
TW202245796A (zh) * 2021-02-04 2022-12-01 大陸商上海森輝醫藥有限公司 糖皮質激素受體激動劑的藥物偶聯物及其在醫藥上的應用
WO2022171101A1 (zh) * 2021-02-10 2022-08-18 映恩生物制药（苏州）有限公司 一种甾体偶联物
AR125079A1 (es) * 2021-03-23 2023-06-07 Lilly Co Eli Agonistas de receptores de glucocorticoides sustituidos con carboxi
TWI899455B (zh) 2021-03-23 2025-10-01 美商美國禮來大藥廠 糖皮質素受體激動劑
AR125084A1 (es) 2021-03-23 2023-06-07 Lilly Co Eli Agonistas del receptor de glucocorticoides novedosos
CN113264983A (zh) * 2021-05-20 2021-08-17 联宁（苏州）生物制药有限公司 一种用于抗体偶联药物的连接子lnd1088的合成方法
CA3222015A1 (en) * 2021-06-01 2022-12-08 Ajinomoto Co., Inc. Conjugates of antibody and functional substance or salts thereof, and compounds used in production of the same or salts thereof
US20250002527A1 (en) * 2021-08-26 2025-01-02 Duality Biologics (Suzhou) Co., Ltd. Steroid compound and conjugate thereof
CN114394933B (zh) * 2022-01-07 2023-08-22 厦门沃克沃德医药科技有限公司 11,12-二氢-γ-氧代-二苯并[f]偶氮-5-(6h)-丁酸的合成方法
WO2023137026A1 (en) 2022-01-12 2023-07-20 Regeneron Pharmaceuticals, Inc. Camptothecin analogs conjugated to a glutamine residue in a protein, and their use
AU2023232169A1 (en) 2022-03-11 2024-10-17 Firefly Bio, Inc. Phenyl maleimide linker agents
CA3253295A1 (en) 2022-05-13 2023-11-16 Eli Lilly And Company HUMAN ALPHA-GLUCOCORTICOID ANTIBODY ANTIBODY AGAINST TUMOR NECROSIS FACTOR
CA3254333A1 (en) * 2022-05-18 2025-07-04 Systimmune, Inc. Ligand-drug conjugate and use thereof
WO2023235738A1 (en) 2022-06-02 2023-12-07 Eli Lilly And Company Human interleukin-4 receptor alpha antibody glucocorticoid conjugates
JP2025524439A (ja) 2022-06-22 2025-07-30 イーライ リリー アンド カンパニー ヒトｃｄ３３抗体及びグルココルチコイドコンジュゲート
CN120239705A (zh) 2022-07-21 2025-07-01 萤火虫生物股份有限公司 糖皮质激素受体激动剂和其缀合物
CN115212315A (zh) * 2022-08-03 2022-10-21 联宁（苏州）生物制药有限公司 一种抗体偶联药物中间体及含有其的抗体偶联药物
IL319768A (en) 2022-09-22 2025-05-01 Lilly Co Eli Glucocorticoid receptor agonists
AU2023407365A1 (en) 2022-12-21 2025-07-31 Regeneron Pharmaceuticals, Inc. Prodrugs of topoisomerase i inhibitor for adc conjugations and methods of use thereof
AU2023416592A1 (en) * 2022-12-28 2025-07-17 Duality Biologics (Shanghai) Co., Ltd. Anti-bdca2 antibody-drug conjugate and use thereof
CN120435486A (zh) * 2023-01-18 2025-08-05 上海盟科药业股份有限公司 用于肾脏疾病靶向治疗的肽-药物偶联物
WO2025014533A1 (en) * 2023-07-10 2025-01-16 Regeneron Pharmaceuticals, Inc. Anti-human cacng1 antibody-drug conjugates and uses thereof

Citations (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0262108A1 (en) 1986-09-25 1988-03-30 Astra Pharmaceutical Production AB A method of controlling the empimeric distribution in the preparation of 16,17-acetals or ketals of pregnane derivatives
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
US5500362A (en) 1987-01-08 1996-03-19 Xoma Corporation Chimeric antibody with specificity to human B cell surface antigen
US5714586A (en) 1995-06-07 1998-02-03 American Cyanamid Company Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates
US5821337A (en) 1991-06-14 1998-10-13 Genentech, Inc. Immunoglobulin variants
US6596541B2 (en) 2000-10-31 2003-07-22 Regeneron Pharmaceuticals, Inc. Methods of modifying eukaryotic cells
WO2005089808A2 (en) 2004-03-15 2005-09-29 Wyeth Antibody calicheamicin conjugates
US20070135398A1 (en) 2005-11-02 2007-06-14 Pierluigi Rossetto Process for the preparation of ciclesonide
US20070258987A1 (en) 2000-11-28 2007-11-08 Seattle Genetics, Inc. Recombinant Anti-Cd30 Antibodies and Uses Thereof
WO2008122039A2 (en) 2007-04-02 2008-10-09 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Selenocysteine mediated hybrid antibody molecules
US20080305497A1 (en) 2007-05-23 2008-12-11 Ventana Medical Systems, Inc. Polymeric carriers for immunohistochemistry and in situ hybridization
WO2010010324A1 (en) 2008-07-21 2010-01-28 Polytherics Limited Novel reagents and method for conjugating biological molecules
US20100129314A1 (en) 2008-04-30 2010-05-27 Immunogen Inc. Potent conjugates and hydrophilic linkers
US7750116B1 (en) 2006-02-18 2010-07-06 Seattle Genetics, Inc. Antibody drug conjugate metabolites
WO2011018611A1 (en) 2009-08-10 2011-02-17 Ucl Business Plc Reversible covalent linkage of functional molecules
WO2011130598A1 (en) 2010-04-15 2011-10-20 Spirogen Limited Pyrrolobenzodiazepines and conjugates thereof
WO2012005982A2 (en) 2010-07-06 2012-01-12 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Reporter for rna polymerase ii termination
US20120096572A1 (en) 2010-08-02 2012-04-19 Regeneron Pharmaceuticals, Inc. Mice That Make VL Binding Proteins
WO2012166559A1 (en) 2011-05-27 2012-12-06 Ambrx, Inc. Compositions containing, methods involving, and uses of non-natural amino acid linked dolastatin derivatives
WO2013055990A1 (en) 2011-10-14 2013-04-18 Seattle Genetics, Inc. Pyrrolobenzodiazepines and targeted conjugates
WO2013053873A1 (en) 2011-10-14 2013-04-18 Spirogen Sàrl Pyrrolobenzodiazepines
WO2013053872A1 (en) 2011-10-14 2013-04-18 Spirogen Sàrl Synthesis method and intermediates useful in the preparation of pyrrolobenzodiazepines
WO2013055993A1 (en) 2011-10-14 2013-04-18 Seattle Genetics, Inc. Pyrrolobenzodiazepines and targeted conjugates
US20130101546A1 (en) 2011-06-10 2013-04-25 Mersana Therapeutics, Inc. Protein-Polymer-Drug Conjugates
WO2013068874A1 (en) 2011-11-11 2013-05-16 Pfizer Inc. Antibody-drug conjugates
WO2013085925A1 (en) 2011-12-05 2013-06-13 Igenica, Inc. Antibody-drug conjugates and related compounds, compositions, and methods
WO2014065661A1 (en) 2012-10-23 2014-05-01 Synaffix B.V. Modified antibody, antibody-conjugate and process for the preparation thereof
WO2014197854A1 (en) 2013-06-06 2014-12-11 Igenica Biotherapeutics, Inc. Novel linkers for antibody-drug conjugates and related compounds, compositions, and methods of use
WO2015071657A1 (en) 2013-11-14 2015-05-21 The University Of Manchester Selective glucocorticoid receptor ligands

Family Cites Families (128)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2737518A (en) * 1955-01-19 1956-03-06 Schering Corp 1-hydroxycortisone, 1-hydroxyhydrocortisone and esters thereof
US2968655A (en) * 1956-11-23 1961-01-17 Upjohn Co 11-oxygenated-6-methyl progesterone and intermediates therefor
US2920999A (en) 1957-06-07 1960-01-12 Pfizer & Co C 21-nitrogen derivatives of corticosteroids
GB889766A (en) 1958-03-04 1962-02-21 Olin Mathieson Improvements in steroids and the synthesis thereof
DE1165595B (de) 1958-03-04 1964-03-19 Olin Mathieson Verfahren zur Herstellung von Triamcinolonacetonid-21-hemisuccinat und dessen Salzen
US3197469A (en) 1958-08-06 1965-07-27 Pharmaceutical Res Products In 16, 17-acetals and ketals of 6-halo-16, 17-dihydroxy steroids of the pregnane seriesand intermediates therefor
US3007923A (en) * 1959-01-22 1961-11-07 Lab Francais Chimiotherapie Process for the fluorination of 9beta, 11beta-epoxy and 5alpha, 6alpha-epoxy steroids
GB898295A (en) 1959-03-18 1962-06-06 Upjohn Co Improvements in or relating to steroids and the manufacture thereof
US3033874A (en) 1960-05-11 1962-05-08 Pfizer & Co C 17beta-propenoyl steroids and process for preparing same
US3033873A (en) 1960-05-11 1962-05-08 Pfizer & Co C 21-aminomethyl-pregnenes
US3020275A (en) * 1960-06-07 1962-02-06 American Cyanamid Co 21-nitrogen substituted steroids of the pregnane series and methods of preparing the same
DE1169444B (de) * 1961-02-22 1964-05-06 Schering Ag Verfahren zur Herstellung von ?-16ª‡-Methylsteroiden
US3047468A (en) * 1961-06-06 1962-07-31 American Cyanamid Co Method of preparing delta1, 4-3-keto steroids of the pregnane series
US3383394A (en) * 1965-08-30 1968-05-14 Schering Corp Novel 17-acylating process and products thereof
US3798216A (en) 1969-03-07 1974-03-19 Fabrication Des Antibiotique S 9-fluoro-11beta,21-dihydroxy-16alpha,17-(2-propenylidenedioxy)-pregna-1,4-diene-3,20-dione and derivatives thereof
DE2047105C3 (de) 1970-09-18 1979-02-15 Schering Ag, 1000 Berlin Und 4619 Bergkamen 17-Chlorsteroide und Verfahren zu ihrer Herstellung
IT1057859B (it) 1972-04-28 1982-03-30 Sigma Tao Ind Farmaceutiche Sp Perivato del triamoinolone
SE378110B (enExample) 1972-05-19 1975-08-18 Bofors Ab
SE378109B (enExample) 1972-05-19 1975-08-18 Bofors Ab
US4076737A (en) 1975-02-20 1978-02-28 Ciba-Geigy Corporation Aldehydes of the pregnane series and derivatives thereof
IL73337A (en) 1984-10-28 1988-09-30 Yissum Res Dev Co Antitumor steroid-platinum complexes and method for the preparation thereof
ES8605537A1 (es) 1985-07-03 1986-02-01 Elmu Sa Procedimiento de obtencion de cetales ciclicos de corticoi- des y sus 21-c esteres
US5116829A (en) * 1990-04-23 1992-05-26 Kao Corporation Steroid compounds
US5183815A (en) 1991-01-22 1993-02-02 Merck & Co., Inc. Bone acting agents
KR960700266A (ko) 1993-01-08 1996-01-19 클래스 빌헬름슨 신규 결장- 또는 회장-특이성 스테로이드 유도체(Novel Colon-or lleum-Specific Steroid Derivatives)
DE4311987A1 (de) 1993-04-07 1994-10-13 Schering Ag Neue Glucocorticoide
US5824669A (en) 1996-03-22 1998-10-20 Nitromed, Inc. Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders
US5837698A (en) 1996-05-02 1998-11-17 G. D. Searle & Co. Steroid nitrite and nitrate ester derivatives useful as anti-inflammatory drugs
WO2000049993A2 (en) 1999-02-24 2000-08-31 Nitromed, Inc. Nitrosated and nitrosylated steroids for the treatment of cardiovascular diseases and disorders
SE0101220D0 (sv) 2001-04-04 2001-04-04 Astrazeneca Ab New use
US6908934B2 (en) 2001-06-11 2005-06-21 Merck & Co., Inc. Therapeutic compounds for treating dyslipidemic conditions
ITMI20020148A1 (it) 2002-01-29 2003-07-29 Nicox Sa Nuovi corticosteroidi
US20050009798A1 (en) 2002-02-20 2005-01-13 Sepracor Inc. Carbonate and carbamate modified forms of glucocorticoids in combination with B2 adrenergic agonists
US7190468B2 (en) 2002-07-17 2007-03-13 Hewlett-Packard Development Company, L.P. Background document rendering system and method
SI1545613T1 (sl) 2002-07-31 2011-11-30 Seattle Genetics Inc Avristatinski konjugati in njihova uporaba za zdravljenje raka avtoimunske bolezni ali infekcijskebolezni
US7985422B2 (en) 2002-08-05 2011-07-26 Torrent Pharmaceuticals Limited Dosage form
EP1562627A4 (en) 2002-08-23 2006-11-02 Mclean Hospital Corp CORTICOSTEROID CONJUGATES AND ITS USES
ATE533513T1 (de) 2002-09-06 2011-12-15 Cerulean Pharma Inc Polymere auf basis von cyclodextrin zur verabreichung von an diese kovalent gebundene arzneimittel
CN1414008A (zh) * 2002-10-17 2003-04-30 南开大学 含氮甾体化合物及其制备方法
US7015349B2 (en) 2003-03-26 2006-03-21 The Gillette Company Reduction of hair growth
DK1725249T3 (en) 2003-11-06 2014-03-17 Seattle Genetics Inc Monomethylvaline compounds capable of conjugating to ligands.
WO2005063777A1 (en) 2003-12-23 2005-07-14 Corus Pharma Benzylphosphate and substituted benzylphosphate prodrugs for the treatment of pulmonary inflammation
US8101714B2 (en) 2004-02-18 2012-01-24 The University Of Georgia Research Foundation, Inc. Teleost derived antimicrobial polypeptides
US20050192257A1 (en) 2004-02-26 2005-09-01 Peyman Gholam A. Predictors for patients at risk for glaucoma from steroid therapy
CN114053429A (zh) 2004-06-01 2022-02-18 健泰科生物技术公司 抗体-药物偶联物和方法
EP1602931A1 (en) 2004-06-03 2005-12-07 Universiteit Leiden SR-A antagonists
US7541330B2 (en) 2004-06-15 2009-06-02 Kosan Biosciences Incorporated Conjugates with reduced adverse systemic effects
ATE411053T1 (de) 2004-08-09 2008-10-15 Deutsches Krebsforsch Albuminkonjugate, die eine glucuron-verknüpfung enthalten
TW200616604A (en) 2004-08-26 2006-06-01 Nicholas Piramal India Ltd Nitric oxide releasing prodrugs containing bio-cleavable linker
JP2008521828A (ja) 2004-11-29 2008-06-26 シアトル ジェネティックス， インコーポレイテッド 操作された抗体およびイムノコンジュゲート
WO2006135371A1 (en) 2005-06-09 2006-12-21 Kosan Biosciences Incorporated Conjugates with reduced adverse systemic effects
CN101227912A (zh) 2005-06-14 2008-07-23 基利得科学公司 用于治疗肺炎和支气管收缩的作为类固醇和β-激动剂的协同前药的取代苯基磷酸酯
KR101352222B1 (ko) 2005-12-22 2014-02-04 백스터 인터내셔널 인코포레이티드 의료용 제품에서 비-내독소 발열성 오염물을 보다 잘검출할 수 있는 개선된 단핵구 활성화 시험
US8354508B2 (en) 2006-07-21 2013-01-15 Diadexus, Inc. PRO115 antibody compositions and methods of use
NZ579067A (en) 2007-02-05 2012-02-24 Nicox Sa Nitric oxide releasing steroids
WO2009002993A1 (en) 2007-06-25 2008-12-31 Endocyte, Inc. Conjugates containing hydrophilic spacer linkers
US20100226987A1 (en) 2007-06-28 2010-09-09 Capsutech Ltd. Targeting conjugates comprising active agents encapsulated in cyclodextrin-containing polymers
CN101397328A (zh) 2007-09-27 2009-04-01 天津药业研究院有限公司 一氧化氮供体型糖皮质激素
PT2214646T (pt) 2007-10-05 2021-09-29 Univ Wayne State Dendrímeros para libertação sustentada de compostos
CL2008003803A1 (es) 2007-12-21 2010-02-19 Schering Corp Compuestos derivados de esteroides c20-21 sustituidos, agonistas del receptor de glucocorticoide; composicion farmaceutica que comprende a dicho compuesto; y uso para tratar o prevenir una enfermedad o afeccion inmune, autoinmune o inflamatoria, tales como colitis inflamatoria y artritis reumatoide.
CN102099368A (zh) * 2007-12-21 2011-06-15 先灵公司 作为糖皮质激素受体激动剂的c-21硫醚
EP2294077A1 (en) 2008-06-10 2011-03-16 Gilead Sciences, Inc. Corticosteroid linked beta-agonist compounds for use in therapy
US9034325B2 (en) 2008-07-22 2015-05-19 Ablynx N.V. Amino acid sequences directed against multitarget scavenger receptors and polypeptides
ES2471145T3 (es) 2009-03-09 2014-06-25 Mikasa Seiyaku Co,. Ltd. Compuesto esteroide
WO2010126953A1 (en) 2009-04-29 2010-11-04 Gilead Sciences, Inc. Corticosteroid linked beta-agonist compounds for use in therapy
WO2010132743A1 (en) 2009-05-15 2010-11-18 Gilead Sciences, Inc. Corticosteroid beta-agonist compounds for use in therapy
WO2011020107A2 (en) 2009-08-14 2011-02-17 Georgetown University Compositions and methods for detection and treatment of breast cancer
GB0917054D0 (en) 2009-09-29 2009-11-11 Cytoguide As Agents, uses and methods
GB0917044D0 (en) 2009-09-29 2009-11-18 Cytoguide As Agents, uses and methods
WO2011081937A1 (en) 2009-12-15 2011-07-07 Gilead Sciences, Inc. Corticosteroid-beta-agonist-muscarinic antagonist compounds for use in therapy
WO2011090940A1 (en) 2010-01-19 2011-07-28 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutic delivery
CA2790203C (en) 2010-02-19 2019-05-14 Norman Latov Inhibitor of macrophage scavenger receptor 1 (msr1) for the treatment of autoimmune demyelinating diseases
CA2806258A1 (en) 2010-07-23 2012-01-26 Takeda Pharmaceutical Company Limited Fused heterocyclic compound and application thereof
CA2809487C (en) 2010-09-01 2019-02-26 Bayer Cropscience Ag N-(tetrazol-5-yl)- and n-(triazol-5-yl)arylcarboxamides and use thereof as herbicides
BR112013010569A2 (pt) 2010-10-29 2017-07-04 Immunogen Inc moléculas de ligação de egfr não antagonísticas e imunoconjugados das mesma
WO2012145632A1 (en) 2011-04-21 2012-10-26 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutic delivery
GB201122325D0 (en) 2011-12-23 2012-02-01 Cytoguide As Novel formulations
WO2013138400A1 (en) 2012-03-14 2013-09-19 Regeneron Pharmaceuticals, Inc. Multispecific antigen-binding molecules and uses thereof
SG11201408347UA (en) 2012-06-14 2015-01-29 Ambrx Inc Anti-psma antibodies conjugated to nuclear receptor ligand polypeptides
US10980860B2 (en) 2012-10-11 2021-04-20 Ascendis Pharma A/S Diagnosis, prevention and treatment of diseases of the joint
KR20150070318A (ko) 2012-10-16 2015-06-24 엔도사이트, 인코포레이티드 비천연 아미노산을 함유하는 약물 전달 컨쥬게이트 및 사용 방법
WO2014065575A1 (ko) 2012-10-25 2014-05-01 주식회사유한양행 4,5-다이하이드로-1h-피라졸 유도체 또는 그의 염 및 이를 포함하는 약학 조성물
SG11201504943QA (en) 2012-12-24 2015-07-30 Abbvie Inc Prolactin receptor binding proteins and uses thereof
AU2014248640B2 (en) 2013-03-13 2018-03-01 Seagen Inc. Cyclodextrin and antibody-drug conjugate formulations
HK1222122A1 (zh) 2013-04-22 2017-06-23 Avelas Biosciences, Inc. 选择性药物递送组合物及使用方法
PL2991683T3 (pl) 2013-05-02 2020-03-31 Glykos Finland Oy Koniugaty glikoproteiny lub glikanu z toksycznym ładunkiem
JP6744212B2 (ja) 2013-06-21 2020-08-19 イナート・ファルマ・ソシエテ・アノニムＩｎｎａｔｅ Ｐｈａｒｍａ Ｐｈａｒｍａ Ｓ．Ａ． ポリペプチドの酵素的結合
US20160158369A1 (en) 2013-07-10 2016-06-09 Seikagaku Corporation Pharmaceutical composition for respiratory administration
TWI641620B (zh) 2013-08-21 2018-11-21 再生元醫藥公司 抗－ｐｒｌｒ抗體及其用途
CA3187392A1 (en) 2013-10-15 2015-04-23 Seagen Inc. Pegylated drug-linkers for improved ligand-drug conjugate pharmacokinetics
CN103694375B (zh) 2013-12-13 2016-10-05 北京大学 一种三萜-环糊精共价化合物及其制备方法和用途
WO2015110609A1 (en) 2014-01-24 2015-07-30 Centre National De La Recherche Scientifique Orally available compounds, a process for preparing the same and their uses as anti-adhesive drugs for treating e. coli induced inflammatory bowel diseases such as crohn's disease
US10550190B2 (en) 2014-04-04 2020-02-04 Merck Sharp & Dohme Corp. Phosphate based linkers for intracellular delivery of drug conjugates
KR20210041126A (ko) 2014-04-10 2021-04-14 다이이찌 산쿄 가부시키가이샤 항her3 항체-약물 콘주게이트
FI3166638T3 (fi) 2014-06-13 2025-09-17 Glykos Finland Oy Hyötykuorma-polymeeri-proteiini konjugaatteja
JP6751393B2 (ja) 2014-12-03 2020-09-02 ジェネンテック， インコーポレイテッド 抗ｓｔａｐｈｙｌｏｃｏｃｃｕｓ ａｕｒｅｕｓ抗体リファマイシン抱合体及びその使用
JP6742314B2 (ja) 2014-12-03 2020-08-19 ジェネンテック， インコーポレイテッド 抗黄色ブドウ球菌抗体リファマイシン複合体及びその使用
EP3230283A1 (en) 2014-12-09 2017-10-18 AbbVie Inc. Bcl-xl inhibitory compounds and antibody drug conjugates including the same
MX2017007629A (es) 2014-12-09 2018-05-17 Abbvie Inc Compuestos inhibidores de bcl-xl que tienen una baja permeabilidad en las celulas y conjugados de anticuerpo-farmaco que los incluyen.
EP3250211B1 (en) 2015-01-30 2021-12-22 Coral Drugs Pvt. Ltd. Novel process for preparation of glucocorticoid steroids
JP2018507844A (ja) 2015-02-06 2018-03-22 ソレント・セラピューティクス・インコーポレイテッドＳｏｒｒｅｎｔｏ Ｔｈｅｒａｐｅｕｔｉｃｓ， Ｉｎｃ． 抗体薬物コンジュゲート
US11191844B2 (en) 2015-07-06 2021-12-07 Regeneran Pharmaceuticals, Inc. Multispecific antigen-binding molecules and uses thereof
WO2017006279A1 (en) 2015-07-08 2017-01-12 Aten Porus Lifesciences Cyclodextrin-polymer complexes and compostions and methods of making and using the same
US10828373B2 (en) 2015-09-10 2020-11-10 Tambo, Inc. Bioorthogonal compositions
EP3359194A4 (en) 2015-10-06 2019-04-24 Merck Sharp & Dohme Corp. ANTIBODY-ACTIVE CONJUGATE FOR ANTI-INFLAMMATORY APPLICATIONS
WO2017132103A2 (en) 2016-01-29 2017-08-03 Merck Sharp & Dohme Corp. Phosphonate linkers and their use to facilitate cellular retention of compounds
WO2017147542A2 (en) 2016-02-26 2017-08-31 Regeneron Pharmaceuticals, Inc. Optimized transglutaminase site-specific antibody conjugation
US11844839B2 (en) 2016-03-25 2023-12-19 Seagen Inc. Process for the preparation of pegylated drug-linkers and intermediates thereof
GB201608936D0 (en) 2016-05-20 2016-07-06 Polytherics Ltd Novel conjugates and novel conjugating reagents
KR102435599B1 (ko) 2016-06-02 2022-08-29 애브비 인코포레이티드 글루코코르티코이드 수용체 작용제 및 이의 면역접합체
WO2017214458A2 (en) 2016-06-08 2017-12-14 Abbvie Inc. Anti-cd98 antibodies and antibody drug conjugates
CA3037732A1 (en) 2016-09-23 2018-03-29 Regeneron Pharmaceuticals, Inc. Anti-steap2 antibodies, antibody-drug conjugates, and bispecific antigen-binding molecules that bind steap2 and cd3, and uses thereof
KR102835535B1 (ko) 2016-11-08 2025-07-18 리제너론 파마슈티칼스 인코포레이티드 스테로이드 및 이의 단백질-접합체
EP3589328A1 (en) 2017-02-28 2020-01-08 Immunogen, Inc. Maytansinoid derivatives with self-immolative peptide linkers and conjugates thereof
CN110944718A (zh) 2017-05-18 2020-03-31 里珍纳龙药品有限公司 环糊精蛋白质药物偶联物
KR20240150809A (ko) 2017-05-18 2024-10-16 리제너론 파마슈티칼스 인코포레이티드 비스-옥타하이드로페난트렌 카복스아미드 및 이의 단백질 접합체
CN111065623B9 (zh) 2017-05-24 2024-10-25 德克萨斯州大学系统董事会 用于抗体药物缀合物的接头
WO2019034176A1 (zh) 2017-08-18 2019-02-21 四川百利药业有限责任公司 一种喜树碱-抗体偶联物
WO2019034177A1 (zh) 2017-08-18 2019-02-21 四川百利药业有限责任公司 具有两种不同药物的抗体药物偶联物
AU2018365946B2 (en) 2017-11-07 2025-08-28 Regeneron Pharmaceuticals, Inc. Hydrophilic linkers for antibody drug conjugates
RS61994B1 (sr) 2017-12-01 2021-07-30 Abbvie Inc Agonist glukokortikoidnog receptora i njegovi imunokonjugati
MX2020006994A (es) 2018-01-08 2020-11-06 Regeneron Pharma Esteroides y conjugados de anticuerpos de los mismos.
MX2020010458A (es) 2018-04-06 2021-01-29 Seattle Genetics Inc Conjugados de camptotecina-peptido.
CN118955710A (zh) 2018-05-09 2024-11-15 里珍纳龙药品有限公司 抗msr1抗体及其使用方法
US12209180B2 (en) 2018-11-20 2025-01-28 Regeneron Pharmaceuticals, Inc. Bis-octahydrophenanthrene carboxamide derivatives and protein conjugates thereof for use as LXR agonists
AU2019403404B2 (en) 2018-12-21 2025-05-29 Regeneron Pharmaceuticals, Inc. Rifamycin analogs and antibody-drug conjugates thereof
CN119264215A (zh) 2019-01-08 2025-01-07 里珍纳龙药品有限公司 无痕连接体及其蛋白质偶联物
US20230119539A1 (en) 2019-01-08 2023-04-20 Regeneron Pharmaceuticals, Inc. Traceless linkers and protein-conjugates thereof

Patent Citations (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0262108A1 (en) 1986-09-25 1988-03-30 Astra Pharmaceutical Production AB A method of controlling the empimeric distribution in the preparation of 16,17-acetals or ketals of pregnane derivatives
US5500362A (en) 1987-01-08 1996-03-19 Xoma Corporation Chimeric antibody with specificity to human B cell surface antigen
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
US5821337A (en) 1991-06-14 1998-10-13 Genentech, Inc. Immunoglobulin variants
US5714586A (en) 1995-06-07 1998-02-03 American Cyanamid Company Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates
US6596541B2 (en) 2000-10-31 2003-07-22 Regeneron Pharmaceuticals, Inc. Methods of modifying eukaryotic cells
US20070258987A1 (en) 2000-11-28 2007-11-08 Seattle Genetics, Inc. Recombinant Anti-Cd30 Antibodies and Uses Thereof
WO2005089808A2 (en) 2004-03-15 2005-09-29 Wyeth Antibody calicheamicin conjugates
US20070135398A1 (en) 2005-11-02 2007-06-14 Pierluigi Rossetto Process for the preparation of ciclesonide
US7750116B1 (en) 2006-02-18 2010-07-06 Seattle Genetics, Inc. Antibody drug conjugate metabolites
WO2008122039A2 (en) 2007-04-02 2008-10-09 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Selenocysteine mediated hybrid antibody molecules
US20080305497A1 (en) 2007-05-23 2008-12-11 Ventana Medical Systems, Inc. Polymeric carriers for immunohistochemistry and in situ hybridization
US20100129314A1 (en) 2008-04-30 2010-05-27 Immunogen Inc. Potent conjugates and hydrophilic linkers
WO2010010324A1 (en) 2008-07-21 2010-01-28 Polytherics Limited Novel reagents and method for conjugating biological molecules
WO2011018611A1 (en) 2009-08-10 2011-02-17 Ucl Business Plc Reversible covalent linkage of functional molecules
WO2011130598A1 (en) 2010-04-15 2011-10-20 Spirogen Limited Pyrrolobenzodiazepines and conjugates thereof
WO2012005982A2 (en) 2010-07-06 2012-01-12 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Reporter for rna polymerase ii termination
US20120096572A1 (en) 2010-08-02 2012-04-19 Regeneron Pharmaceuticals, Inc. Mice That Make VL Binding Proteins
WO2012166559A1 (en) 2011-05-27 2012-12-06 Ambrx, Inc. Compositions containing, methods involving, and uses of non-natural amino acid linked dolastatin derivatives
US20130101546A1 (en) 2011-06-10 2013-04-25 Mersana Therapeutics, Inc. Protein-Polymer-Drug Conjugates
WO2013053872A1 (en) 2011-10-14 2013-04-18 Spirogen Sàrl Synthesis method and intermediates useful in the preparation of pyrrolobenzodiazepines
WO2013053873A1 (en) 2011-10-14 2013-04-18 Spirogen Sàrl Pyrrolobenzodiazepines
WO2013055993A1 (en) 2011-10-14 2013-04-18 Seattle Genetics, Inc. Pyrrolobenzodiazepines and targeted conjugates
WO2013055990A1 (en) 2011-10-14 2013-04-18 Seattle Genetics, Inc. Pyrrolobenzodiazepines and targeted conjugates
WO2013068874A1 (en) 2011-11-11 2013-05-16 Pfizer Inc. Antibody-drug conjugates
WO2013085925A1 (en) 2011-12-05 2013-06-13 Igenica, Inc. Antibody-drug conjugates and related compounds, compositions, and methods
WO2014065661A1 (en) 2012-10-23 2014-05-01 Synaffix B.V. Modified antibody, antibody-conjugate and process for the preparation thereof
WO2014197854A1 (en) 2013-06-06 2014-12-11 Igenica Biotherapeutics, Inc. Novel linkers for antibody-drug conjugates and related compounds, compositions, and methods of use
WO2015071657A1 (en) 2013-11-14 2015-05-21 The University Of Manchester Selective glucocorticoid receptor ligands

Non-Patent Citations (29)

* Cited by examiner, † Cited by third party
Title
"Improved Dual-Luciferase Reporter Assays for Nuclear Receptors", CURRENT CHEM GENOMICS, vol. 4, 2010, pages 43 - 49
AAPS JOURNAL, vol. 17, no. 2, March 2015 (2015-03-01)
AGARWAL ET AL., PROC. NATL. ACAD. SCI., vol. 110, 2013, pages 46 - 51
ANGAL ET AL., MOLECULAR IMMUNOLOGY, vol. 30, 1993, pages 105
BASKIN, J. M.PRESCHER, J. A.LAUGHLIN, S. TAGARD, N. J.CHANG, P. VMILLER, I. A.LO, A.CODELLI, J. A.BERTOZZI, C. R., PNAS, vol. 104, no. 43, 2007, pages 16793 - 7
BERGE ET AL.: "Pharmaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1, XP002675560, DOI: 10.1002/jps.2600660104
BIOORG. MED. CHEM. LETT., vol. 25, 2015, pages 2837 - 2843
CARBOHYDRATE RESEARCH, vol. 146, 1986, pages 241 - 249
CARRICO ET AL., NAT. CHEM. BIOL., vol. 3, 2007, pages 321 - 322
CLYNES ET AL., PROC., vol. 95, 1998, pages 652 - 656
DENNLER ET AL., BIOCONJUGATE CHEM., vol. 25, 2014, pages 569 - 578
DRUG DELIV., vol. 23, no. 5, June 2016 (2016-06-01), pages 1662 - 6
HOFER ET AL., PROC. NATL. ACAD. SCI., vol. 105, 2008, pages 12451 - 12456
HOLLANDER ET AL., BIOCONJUGATE CHEM., vol. 19, 2008, pages 358 - 361
INT. J. MOL. SCI., vol. 17, 2016, pages 561
J. AM. CHEM. SOC., vol. 115, no. 12, 1993, pages 5035 - 5040
J. AM. CHEM. SOC., vol. 128, no. 12, 2006, pages 4023 - 4034
J. AM. CHEM. SOC., vol. 134, no. 46, 2012, pages 19108 - 19117
J. MED. CHEM., vol. 40, no. 17, 1997, pages 2755 - 2761
J. ORG. CHEM., vol. 75, 2010, pages 627 - 636
J. PHARMACOL., vol. 172, 2015, pages 1360
MOLPHARM., vol. 12, no. 6, 1 June 2015 (2015-06-01), pages 1863 - 71
ORG. BIOMOL. CHEM., vol. 12, 2014, pages 7551 - 7560
RABUKA ET AL., NAT. PROTOCOLS, vol. 10, 2012, pages 1052 - 1067
RYAN ET AL., FOOD & AGRICULTURE IMMUNOL., vol. 13, 2001, pages 127 - 130
SHAUNAK ET AL., NAT. CHEM. BIOL., vol. 2, 2006, pages 312 - 313
SYNTH. COMMUN., vol. 32, no. 21, 2002, pages 3367 - 3372
SYNTHESIS, vol. 18, 2011, pages 2935 - 2940
TAYLOR ET AL., NUCL. ACIDS RES., vol. 20, 1992, pages 6287 - 6295

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